rs142094977

Variant names:

• chr22-36286827-A-G
• rs142094977
• NM_002473.6:c.4952T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.4952T>C​(p.Met1651Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,609,558 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1651I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.54
• Publications: 9 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]

MIR6819 (HGNC:50155): (microRNA 6819) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0889076).
• BP6: Variant 22-36286827-A-G is Benign according to our data. Variant chr22-36286827-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00156 (237/152344) while in subpopulation NFE AF = 0.00306 (208/68036). AF 95% confidence interval is 0.00272. There are 0 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 237 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.4952T>C	p.Met1651Thr	missense	Exon 35 of 41	NP_002464.1	P35579-1
	MIR6819	NR_106877.1		n.*20T>C		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.4952T>C	p.Met1651Thr	missense	Exon 35 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.5015T>C	p.Met1672Thr	missense	Exon 36 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.5015T>C	p.Met1672Thr	missense	Exon 36 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00128 AC: 318 AN: 247730 AF XY: 0.00119

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00147

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00168 AC: 2443 AN: 1457214 Hom.: 2 Cov.: 32 AF XY: 0.00169 AC XY: 1225 AN XY: 725148

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

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00117 AC: 57 AN: 48806

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00202 AC: 2251 AN: 1111972

Other (OTH) AF: 0.00136 AC: 82 AN: 60376

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74506

African (AFR) AF: 0.000265 AC: 11 AN: 41572

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00306 AC: 208 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00202 Hom.: 1

Bravo AF: 0.000994

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00128 AC: 156

EpiCase AF: 0.00196

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	MYH9-related disorder (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.092
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.64	N
PhyloP100		2.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.45
Sift	Benign	0.13	T
Sift4G	Benign	0.076	T
Polyphen		0.0070	B
Vest4		0.85
MVP		0.94
MPC		0.59
ClinPred		0.026	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.22
Mutation Taster		=29/71	disease causing

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: rs142094977; hg19: chr22-36682873;