rs542791128

chr22-36294232-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):c.3697G>A(p.Val1233Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,614,126 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (7 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.62

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH9
• BP4: Computational evidence support a benign effect (MetaRNN=0.009485006).
• BP6: Variant 22-36294232-C-T is Benign according to our data. Variant chr22-36294232-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36294232-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000289 (44/152318) while in subpopulation SAS AF= 0.00849 (41/4828). AF 95% confidence interval is 0.00643. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.3697G>A	p.Val1233Met	missense_variant	28/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11	c.3697G>A	p.Val1233Met	missense_variant	28/41	1	NM_002473.6	P1
MYH9	ENST00000685801.1	c.3760G>A	p.Val1254Met	missense_variant	29/42
MYH9	ENST00000691109.1	n.3992G>A		non_coding_transcript_exon_variant	22/35

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000816 AC: 205 AN: 251376 Hom.: 1 AF XY: 0.00115 AC XY: 156 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000430 AC: 628 AN: 1461808 Hom.: 7 Cov.: 35 AF XY: 0.000628 AC XY: 457 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00628

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74492

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000742 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.000955 AC: 116

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 26, 2017

p.Val1233Met variant in exon 28 of MYH9: This variant is not expected to have cl inical significance because it has been identified in 0.6% (179/30782) of South Asian chromosomes including 1 homozygote in the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org; dbSNP rs542791128), and in 2.9% (6/206) o f GIH Indian chromosomes by the 1000 Genomes Project. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.26
Sift	Benign	0.079	T
Sift4G	Benign	0.23	T
Polyphen		0.13	B
Vest4		0.56
MVP		0.65
MPC		0.55
ClinPred		0.035	T
GERP RS		5.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.12
gMVP		0.15

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: rs542791128; hg19: chr22-36690278;