rs113698937

Positions:

• chr22-36293875-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.3838-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,609,590 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (45 hom.)
• Consequence: MYH9 NM_002473.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001940
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.95

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-36293875-G-A is Benign according to our data. Variant chr22-36293875-G-A is described in ClinVar as [Benign]. Clinvar id is 44560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36293875-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2146/152194) while in subpopulation AFR AF= 0.0474 (1968/41516). AF 95% confidence interval is 0.0457. There are 54 homozygotes in gnomad4. There are 995 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2146 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH9	NM_002473.6	c.3838-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.3838-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002473.6	ENSP00000216181	P1
MYH9	ENST00000685801.1	c.3901-12C>T		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000510688
MYH9	ENST00000691109.1	n.4133-12C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2143 AN: 152076 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00450 AC: 1093 AN: 242704 Hom.: 18 AF XY: 0.00344 AC XY: 452 AN XY: 131560

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.0000486

Gnomad NFE exome AF: 0.000557

Gnomad OTH exome AF: 0.00320

GnomAD4 exome AF: 0.00192 AC: 2796 AN: 1457396 Hom.: 45 Cov.: 32 AF XY: 0.00170 AC XY: 1235 AN XY: 724826

Gnomad4 AFR exome AF: 0.0462

Gnomad4 AMR exome AF: 0.00478

Gnomad4 ASJ exome AF: 0.00987

Gnomad4 EAS exome AF: 0.0000760

Gnomad4 SAS exome AF: 0.000303

Gnomad4 FIN exome AF: 0.0000571

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.0141 AC: 2146 AN: 152194 Hom.: 54 Cov.: 32 AF XY: 0.0134 AC XY: 995 AN XY: 74400

Gnomad4 AFR AF: 0.0474

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00876 Hom.: 3

Bravo AF: 0.0162

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	3838-12C>T in Intron 28 of MYH9: This variant is not expected to have clinical s ignificance because it has been identified in 3.9% (145/3736) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs113698937). -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

MYH9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.84
CADD	Benign	0.0070
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0080
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

Publications

LitVar

Other links and lift over

dbSNP: rs113698937; hg19: chr22-36689921;