rs16996648

Variant names:

• chr22-36296706-T-C
• rs16996648
• NM_002473.6:c.3272+137A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002473.6(MYH9):​c.3272+137A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,011,364 control chromosomes in the GnomAD database, including 2,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.087 (1610 hom., cov: 32)
  • Exomes 𝑓: 0.019 (1024 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.39
• Publications: 10 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: G2P, Labcorp Genetics (formerly Invitae)
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-36296706-T-C is Benign according to our data. Variant chr22-36296706-T-C is described in ClinVar as Benign. ClinVar VariationId is 1235000.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.3272+137A>G		intron_variant	Intron 25 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.3272+137A>G		intron_variant	Intron 25 of 40	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.3335+137A>G		intron_variant	Intron 26 of 41			ENSP00000510688.1
MYH9	ENST00000459960.1	n.481+137A>G		intron_variant	Intron 1 of 1	2
MYH9	ENST00000691109.1	n.3567+137A>G		intron_variant	Intron 19 of 34

Frequencies

GnomAD3 genomes AF: 0.0873 AC: 13277 AN: 152072 Hom.: 1607 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0392

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.0589

GnomAD4 exome AF: 0.0195 AC: 16730 AN: 859174 Hom.: 1024 AF XY: 0.0184 AC XY: 7870 AN XY: 427932

African (AFR) AF: 0.286 AC: 5683 AN: 19868

American (AMR) AF: 0.0260 AC: 477 AN: 18318

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 299 AN: 16166

East Asian (EAS) AF: 0.0000307 AC: 1 AN: 32540

South Asian (SAS) AF: 0.00954 AC: 498 AN: 52222

European-Finnish (FIN) AF: 0.0189 AC: 566 AN: 30026

Middle Eastern (MID) AF: 0.0669 AC: 185 AN: 2764

European-Non Finnish (NFE) AF: 0.0122 AC: 7906 AN: 647874

Other (OTH) AF: 0.0283 AC: 1115 AN: 39396

GnomAD4 genome AF: 0.0873 AC: 13290 AN: 152190 Hom.: 1610 Cov.: 32 AF XY: 0.0849 AC XY: 6318 AN XY: 74410

African (AFR) AF: 0.274 AC: 11345 AN: 41456

American (AMR) AF: 0.0392 AC: 600 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10616

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 884 AN: 68020

Other (OTH) AF: 0.0582 AC: 123 AN: 2112

Alfa AF: 0.0304 Hom.: 553

Bravo AF: 0.0969

Asia WGS AF: 0.0190 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.074
DANN	Benign	0.46
PhyloP100		-4.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs16996648; hg19: chr22-36692752;