chr22-36316918-A-G

Variant names:

• chr22-36316918-A-G
• rs1557538
• NM_002473.6:c.1228-249T>C

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.1228-249T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 143,450 control chromosomes in the GnomAD database, including 24,735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.56 (24735 hom., cov: 31)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0380
• Publications: 5 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 22-36316918-A-G is Benign according to our data. Variant chr22-36316918-A-G is described in ClinVar as Benign. ClinVar VariationId is 1181576.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.684 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.1228-249T>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.1228-249T>C		intron	N/A	ENSP00000216181.6
	MYH9	ENST00000685801.1		c.1228-249T>C		intron	N/A	ENSP00000510688.1
	MYH9	ENST00000477189.1	TSL:2	n.416-249T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.563 AC: 80635 AN: 143340 Hom.: 24729 Cov.: 31

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.530

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.589

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

GnomAD4 genome AF: 0.562 AC: 80661 AN: 143450 Hom.: 24735 Cov.: 31 AF XY: 0.556 AC XY: 39056 AN XY: 70194

African (AFR) AF: 0.361 AC: 13773 AN: 38192

American (AMR) AF: 0.628 AC: 9059 AN: 14422

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1898 AN: 3312

East Asian (EAS) AF: 0.200 AC: 1022 AN: 5114

South Asian (SAS) AF: 0.390 AC: 1826 AN: 4686

European-Finnish (FIN) AF: 0.654 AC: 6551 AN: 10012

Middle Eastern (MID) AF: 0.532 AC: 150 AN: 282

European-Non Finnish (NFE) AF: 0.690 AC: 44557 AN: 64602

Other (OTH) AF: 0.583 AC: 1165 AN: 1998

Alfa AF: 0.603 Hom.: 9332

Bravo AF: 0.564

Asia WGS AF: 0.245 AC: 819 AN: 3348

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.65
PhyloP100		0.038
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: rs1557538; hg19: chr22-36712963;