2-191390444-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2

The NM_001130158.3(MYO1B):c.1934A>G(p.Tyr645Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MYO1B
NM_001130158.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

MYO1B (HGNC:7596): (myosin IB) Enables ATP binding activity; actin filament binding activity; and microfilament motor activity. Involved in actin filament organization and post-Golgi vesicle-mediated transport. Located in several cellular components, including actin filament; endosome; and perinuclear region of cytoplasm. Colocalizes with trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

MYO1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP2

Missense variant where missense usually causes diseases, MYO1B

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

BS2

High AC in GnomAdExome at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1B	NM_001130158.3 linkuse as main transcript	c.1934A>G	p.Tyr645Cys	missense_variant	18/31	ENST00000392318.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1B	ENST00000392318.8 linkuse as main transcript	c.1934A>G	p.Tyr645Cys	missense_variant	18/31	1	NM_001130158.3	P1	O43795-1
MYO1B	ENST00000304164.8 linkuse as main transcript	c.1934A>G	p.Tyr645Cys	missense_variant	18/31	1		P1	O43795-1
MYO1B	ENST00000339514.8 linkuse as main transcript	c.1934A>G	p.Tyr645Cys	missense_variant	18/29	1			O43795-2
MYO1B	ENST00000392316.5 linkuse as main transcript	c.1934A>G	p.Tyr645Cys	missense_variant	17/29	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251374

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.1934A>G (p.Y645C) alteration is located in exon 18 (coding exon 17) of the MYO1B gene. This alteration results from a A to G substitution at nucleotide position 1934, causing the tyrosine (Y) at amino acid position 645 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.49

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;H;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-8.8

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.94

MutPred

0.88

Gain of methylation at K646 (P = 0.0132);Gain of methylation at K646 (P = 0.0132);Gain of methylation at K646 (P = 0.0132);Gain of methylation at K646 (P = 0.0132);

MVP

0.89

MPC

1.2

ClinPred

0.99

GERP RS

5.4

Varity_R

0.87

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over