chr22-36296899-C-T

Variant names:

• chr22-36296899-C-T
• rs139441456
• NM_002473.6:c.3216G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002473.6(MYH9):​c.3216G>A​(p.Ala1072Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000469 in 1,613,552 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (4 hom.)
• Consequence: MYH9 NM_002473.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.37
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 22-36296899-C-T is Benign according to our data. Variant chr22-36296899-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000559 (85/152186) while in subpopulation NFE AF = 0.00106 (72/68036). AF 95% confidence interval is 0.000861. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 85 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.3216G>A	p.Ala1072Ala	synonymous	Exon 25 of 41	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.3216G>A	p.Ala1072Ala	synonymous	Exon 25 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.3279G>A	p.Ala1093Ala	synonymous	Exon 26 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.3279G>A	p.Ala1093Ala	synonymous	Exon 26 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000415 AC: 104 AN: 250894 AF XY: 0.000479

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000604

Gnomad NFE exome AF: 0.000706

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000459 AC: 671 AN: 1461366 Hom.: 4 Cov.: 31 AF XY: 0.000486 AC XY: 353 AN XY: 726936

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86244

European-Finnish (FIN) AF: 0.000677 AC: 36 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000519 AC: 577 AN: 1111786

Other (OTH) AF: 0.000464 AC: 28 AN: 60378

GnomAD4 genome AF: 0.000559 AC: 85 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000498 AC XY: 37 AN XY: 74352

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000853 Hom.: 0

Bravo AF: 0.000393

EpiCase AF: 0.000709

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	MYH9-related disorder (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.057
DANN	Benign	0.72
PhyloP100		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs139441456; hg19: chr22-36692945; COSMIC: COSV53392630; COSMIC: COSV53392630;