rs201691359

Variant names:

• chr22-36321743-G-A
• rs201691359
• NM_002473.6:c.769+15C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-36321743-G-A
• chr22-36321743-G-C
• chr22-36321743-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.769+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,612,878 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.31
• Publications: 1 publications found

Genes affected

MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

MYH9 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• May-Hegglin anomaly

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 22-36321743-G-A is Benign according to our data. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36321743-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000446 (68/152320) while in subpopulation AMR AF = 0.00176 (27/15300). AF 95% confidence interval is 0.00124. There are 1 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.769+15C>T		intron_variant	Intron 7 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.769+15C>T		intron_variant	Intron 7 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000465 AC: 117 AN: 251488 AF XY: 0.000427

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.000303 AC: 443 AN: 1460558 Hom.: 2 Cov.: 31 AF XY: 0.000312 AC XY: 227 AN XY: 726686

African (AFR) AF: 0.000120 AC: 4 AN: 33450

American (AMR) AF: 0.00127 AC: 57 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86218

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53396

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.000279 AC: 310 AN: 1110844

Other (OTH) AF: 0.000514 AC: 31 AN: 60342

GnomAD4 genome AF: 0.000446 AC: 68 AN: 152320 Hom.: 1 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74498

African (AFR) AF: 0.000144 AC: 6 AN: 41564

American (AMR) AF: 0.00176 AC: 27 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.000684

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jun 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.769+15C>T in intron 07 of MYH9: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 39/66728 of European chromosomes and in 16/1157 8 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs201691359). -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1

Nov 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH9-related disorder Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.071
DANN	Benign	0.73
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201691359; hg19: chr22-36717788;