NM_002473.6:c.1381-178T>C

Variant names:

• chr22-36314496-A-G
• rs4820232
• NM_002473.6:c.1381-178T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002473.6(MYH9):​c.1381-178T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 152,074 control chromosomes in the GnomAD database, including 24,211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.54 (24211 hom., cov: 33)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.41
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-36314496-A-G is Benign according to our data. Variant chr22-36314496-A-G is described in ClinVar as Benign. ClinVar VariationId is 1275620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.1381-178T>C		intron	N/A	NP_002464.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.1381-178T>C		intron	N/A	ENSP00000216181.6
	MYH9	ENST00000685801.1		c.1381-178T>C		intron	N/A	ENSP00000510688.1
	MYH9	ENST00000955568.1		c.1381-178T>C		intron	N/A	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81585 AN: 151956 Hom.: 24213 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.676

Gnomad OTH AF: 0.559

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.537 AC: 81594 AN: 152074 Hom.: 24211 Cov.: 33 AF XY: 0.532 AC XY: 39526 AN XY: 74336

African (AFR) AF: 0.301 AC: 12477 AN: 41464

American (AMR) AF: 0.615 AC: 9392 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1832 AN: 3468

East Asian (EAS) AF: 0.223 AC: 1153 AN: 5178

South Asian (SAS) AF: 0.387 AC: 1864 AN: 4822

European-Finnish (FIN) AF: 0.653 AC: 6908 AN: 10578

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.676 AC: 45952 AN: 67970

Other (OTH) AF: 0.554 AC: 1166 AN: 2106

Alfa AF: 0.535 Hom.: 2614

Bravo AF: 0.526

Asia WGS AF: 0.259 AC: 900 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.37
DANN	Benign	0.44
PhyloP100		-1.4
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: rs4820232; hg19: chr22-36710541;