rs147122501

Variant names:

• chr22-36349101-G-A
• rs147122501
• NM_002473.6:c.136C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.136C>T​(p.Leu46Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,614,202 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L46L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (62 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 0.602
• Publications: 15 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_002473.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.009099573).
• BP6: Variant 22-36349101-G-A is Benign according to our data. Variant chr22-36349101-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178438.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 = 0.00521 (793/152314) while in subpopulation NFE AF = 0.00395 (269/68038). AF 95% confidence interval is 0.00356. There are 12 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 793 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.136C>T	p.Leu46Phe	missense	Exon 2 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.136C>T	p.Leu46Phe	missense	Exon 2 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000401701.1	TSL:1	c.136C>T	p.Leu46Phe	missense	Exon 2 of 6	ENSP00000384631.1	Q5BKV1
	MYH9	ENST00000685801.1		c.136C>T	p.Leu46Phe	missense	Exon 2 of 42	ENSP00000510688.1	A0A8I5KWT8

Frequencies

GnomAD3 genomes AF: 0.00521 AC: 793 AN: 152196 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00604 AC: 1519 AN: 251398 AF XY: 0.00601

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00445 AC: 6503 AN: 1461888 Hom.: 62 Cov.: 34 AF XY: 0.00435 AC XY: 3167 AN XY: 727242

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.0383 AC: 2046 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00379 AC: 4215 AN: 1112006

Other (OTH) AF: 0.00267 AC: 161 AN: 60396

GnomAD4 genome AF: 0.00521 AC: 793 AN: 152314 Hom.: 12 Cov.: 32 AF XY: 0.00699 AC XY: 521 AN XY: 74482

African (AFR) AF: 0.000553 AC: 23 AN: 41570

American (AMR) AF: 0.000523 AC: 8 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0459 AC: 487 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00395 AC: 269 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00328 Hom.: 1

Bravo AF: 0.00187

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00526 AC: 639

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	5	not specified (5)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)
-	-	1	MYH9-related disorder (1)
-	-	-	Autosomal dominant nonsyndromic hearing loss 17;C4551953:Vitelliform macular dystrophy 1;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.60
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.89	P
Vest4		0.30
MVP		0.74
MPC		1.5
ClinPred		0.028	T
GERP RS		5.3
Varity_R		0.31
gMVP		0.74
Mutation Taster		=85/15	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: rs147122501; hg19: chr22-36745146;