22-36309402-G-A

Variant names:

• chr22-36309402-G-A
• rs9622375
• NM_002473.6:c.1729-6C>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.1729-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,611,984 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (15 hom.)
• Consequence: MYH9 NM_002473.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002602
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.44
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.87).
• BP6: Variant 22-36309402-G-A is Benign according to our data. Variant chr22-36309402-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00677 (1032/152328) while in subpopulation AFR AF = 0.0222 (922/41568). AF 95% confidence interval is 0.021. There are 18 homozygotes in GnomAd4. There are 466 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1032 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002473.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.1729-6C>T		splice_region intron	N/A	NP_002464.1	P35579-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.1729-6C>T		splice_region intron	N/A	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.1729-6C>T		splice_region intron	N/A	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.1729-6C>T		splice_region intron	N/A	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.00679 AC: 1033 AN: 152210 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00244 AC: 612 AN: 251170 AF XY: 0.00204

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00105 AC: 1534 AN: 1459656 Hom.: 15 Cov.: 31 AF XY: 0.000973 AC XY: 707 AN XY: 726256

African (AFR) AF: 0.0228 AC: 761 AN: 33428

American (AMR) AF: 0.00235 AC: 105 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 256 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5764

European-Non Finnish (NFE) AF: 0.000178 AC: 198 AN: 1110008

Other (OTH) AF: 0.00318 AC: 192 AN: 60346

GnomAD4 genome AF: 0.00677 AC: 1032 AN: 152328 Hom.: 18 Cov.: 33 AF XY: 0.00626 AC XY: 466 AN XY: 74498

African (AFR) AF: 0.0222 AC: 922 AN: 41568

American (AMR) AF: 0.00281 AC: 43 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68022

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00412 Hom.: 2

Bravo AF: 0.00794

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (1)
-	-	1	Kidney disorder (1)
-	-	1	MYH9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.6
DANN	Benign	0.65
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0
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: rs9622375; hg19: chr22-36705447;