rs372760228

Variant names:

• chr12-57029508-A-G
• rs372760228
• NM_005379.4:c.2804T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-57029508-A-G
• chr12-57029508-A-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005379.4(MYO1A):​c.2804T>C​(p.Ile935Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000206 in 1,614,166 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.76
• Publications: 3 publications found

Genes affected

MYO1A (HGNC:7595): (myosin IA) This gene encodes a member of the myosin superfamily. The protein represents an unconventional myosin; it should not be confused with the conventional skeletal muscle myosin-1 (MYH1). Unconventional myosins contain the basic domains characteristic of conventional myosins and are further distinguished from class members by their tail domains. They function as actin-based molecular motors. Mutations in this gene have been associated with autosomal dominant deafness. Alternatively spliced variants have been found for this gene. [provided by RefSeq, Dec 2011]

MYO1A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 12-57029508-A-G is Benign according to our data. Variant chr12-57029508-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164580.
• BS2: High AC in GnomAd4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005379.4. 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
	MYO1A	NM_005379.4	MANE Select	c.2804T>C	p.Ile935Thr	missense	Exon 26 of 28	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.2804T>C	p.Ile935Thr	missense	Exon 27 of 29	NP_001242970.1	Q9UBC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1A	ENST00000300119.8	TSL:1 MANE Select	c.2804T>C	p.Ile935Thr	missense	Exon 26 of 28	ENSP00000300119.3	Q9UBC5
	MYO1A	ENST00000442789.6	TSL:1	c.2804T>C	p.Ile935Thr	missense	Exon 27 of 29	ENSP00000393392.2	Q9UBC5
	MYO1A	ENST00000907120.1		c.2936T>C	p.Ile979Thr	missense	Exon 26 of 28	ENSP00000577179.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000251 AC: 63 AN: 251314 AF XY: 0.000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000213 AC: 312 AN: 1461892 Hom.: 3 Cov.: 33 AF XY: 0.000234 AC XY: 170 AN XY: 727248

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

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

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000190 AC: 211 AN: 1112010

Other (OTH) AF: 0.000315 AC: 19 AN: 60396

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74460

African (AFR) AF: 0.0000481 AC: 2 AN: 41558

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000204 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.28
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.91	P
Vest4		0.57
MVP		0.56
MPC		0.34
ClinPred		0.47	T
GERP RS		4.5
Varity_R		0.25
gMVP		0.52
Mutation Taster		=69/31	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: rs372760228; hg19: chr12-57423292;