rs145429636

Variant names:

• chr22-36293871-G-A
• rs145429636
• NM_002473.6:c.3838-8C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-36293871-G-A
• chr22-36293871-G-T

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.3838-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,610,612 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (116 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (127 hom.)
• Consequence: MYH9 NM_002473.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002491
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.582
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-36293871-G-A is Benign according to our data. Variant chr22-36293871-G-A is described in ClinVar as Benign. ClinVar VariationId is 44561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0715 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.3838-8C>T		splice_region intron	N/A	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.3838-8C>T		splice_region intron	N/A	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.3901-8C>T		splice_region intron	N/A	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.3901-8C>T		splice_region intron	N/A	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3265 AN: 152052 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00574 AC: 1403 AN: 244632 AF XY: 0.00415

Gnomad AFR exome AF: 0.0805

Gnomad AMR exome AF: 0.00358

Gnomad ASJ exome AF: 0.000606

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000815

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00216 AC: 3146 AN: 1458442 Hom.: 127 Cov.: 32 AF XY: 0.00186 AC XY: 1346 AN XY: 725400

African (AFR) AF: 0.0760 AC: 2539 AN: 33400

American (AMR) AF: 0.00457 AC: 203 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.000652 AC: 17 AN: 26056

East Asian (EAS) AF: 0.000228 AC: 9 AN: 39560

South Asian (SAS) AF: 0.000151 AC: 13 AN: 85812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52658

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5756

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1110516

Other (OTH) AF: 0.00468 AC: 282 AN: 60258

GnomAD4 genome AF: 0.0214 AC: 3261 AN: 152170 Hom.: 116 Cov.: 32 AF XY: 0.0212 AC XY: 1576 AN XY: 74404

African (AFR) AF: 0.0737 AC: 3057 AN: 41496

American (AMR) AF: 0.0104 AC: 159 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68008

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

Alfa AF: 0.0120 Hom.: 31

Bravo AF: 0.0254

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	MYH9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.90
DANN	Benign	0.81
PhyloP100		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0040
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: rs145429636; hg19: chr22-36689917;