rs1556631812

Positions:

• chr22-36296900-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002473.6(MYH9):​c.3215C>T​(p.Ala1072Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH9. . Gene score misZ 3.473 (greater than the threshold 3.09). Trascript score misZ 6.1231 (greater than threshold 3.09). GenCC has associacion of gene with May-Hegglin anomaly, autosomal dominant nonsyndromic hearing loss, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, autosomal dominant nonsyndromic hearing loss 17.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH9	NM_002473.6	c.3215C>T	p.Ala1072Val	missense_variant	25/41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.3215C>T	p.Ala1072Val	missense_variant	25/41	1	NM_002473.6	ENSP00000216181	P1
MYH9	ENST00000685801.1	c.3278C>T	p.Ala1093Val	missense_variant	26/42			ENSP00000510688
MYH9	ENST00000459960.1	n.424C>T		non_coding_transcript_exon_variant	1/2	2
MYH9	ENST00000691109.1	n.3510C>T		non_coding_transcript_exon_variant	19/35

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461394 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 2017

The p.Ala1072Val variant in MYH9 has not been previously reported in individuals with hearing loss or MYH9-related disorders, or in large population studies. Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. In summary, the clinical significa nce of the p.Ala1072Val variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.077	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.37
Sift	Benign	0.035	D
Sift4G	Uncertain	0.059	T
Polyphen		0.89	P
Vest4		0.48
MutPred		0.38		Gain of catalytic residue at A1072 (P = 0.0014);
MVP		0.72
MPC		1.4
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556631812; hg19: chr22-36692946; COSMIC: COSV53392004; COSMIC: COSV53392004;