chr12-57029508-A-G

Position:

• chr12-57029508-A-G

Variant summary

Our verdict is Likely benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 164580.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO1A	NM_005379.4	c.2804T>C	p.Ile935Thr	missense_variant	26/28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2	c.2804T>C	p.Ile935Thr	missense_variant	27/29		NP_001242970.1
MYO1A	XM_047428876.1	c.2804T>C	p.Ile935Thr	missense_variant	27/29		XP_047284832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO1A	ENST00000300119.8	c.2804T>C	p.Ile935Thr	missense_variant	26/28	1	NM_005379.4	ENSP00000300119.3

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

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251314 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135810

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 SAS exome AF: 0.000196

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

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.000315

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

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYO1A: BP4, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 16, 2013

The Ile935Thr variant in MYO1A has been identified by our laboratory in one indi vidual with hearing loss; however this individual had an alternate genetic expla nation for their clinical features. This variant has not been reported in large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Ile935Thr variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

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;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;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.91	P;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs372760228; hg19: chr12-57423292;