Variant 2-70297444-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_StrongBP6_Moderate

The NM_001329752.2(FAM136A):c.583G>C(p.Asp195His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.068 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM136A
NM_001329752.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.20

Variant links:

Genes affected

FAM136A (HGNC:25911): (family with sequence similarity 136 member A) This gene encodes a mitochondrially localized protein that is highly conserved across species. The gene is expressed in a variety of tissues including human lymphoblast cells and rat neurosensorial epithelium of the cristaampullaris. A mutation in this gene has been associated with familial Meniere's disease, a chronic disorder of the inner ear. Several pseudogenes of this gene are found on other chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

FAM136A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.010998726).

BP6

Variant 2-70297444-C-G is Benign according to our data. Variant chr2-70297444-C-G is described in ClinVar as [Benign]. Clinvar id is 3055771.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM136A	NM_001329752.2 linkuse as main transcript	c.583G>C	p.Asp195His	missense_variant	3/3	ENST00000430566.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM136A	ENST00000430566.6 linkuse as main transcript	c.583G>C	p.Asp195His	missense_variant	3/3	3	NM_001329752.2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

3253

AN:

128200

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.0551

Gnomad AMR

AF:

0.0334

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.0295

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.0249

Gnomad MID

AF:

0.0115

Gnomad NFE

AF:

0.0300

Gnomad OTH

AF:

0.0284

GnomAD3 exomes

AF:

0.00278

AC:

606

AN:

218350

Hom.:

AF XY:

0.00250

AC XY:

295

AN XY:

117952

show subpopulations

Gnomad AFR exome

AF:

0.000791

Gnomad AMR exome

AF:

0.00760

Gnomad ASJ exome

AF:

0.00393

Gnomad EAS exome

AF:

0.00159

Gnomad SAS exome

AF:

0.00189

Gnomad FIN exome

AF:

0.000906

Gnomad NFE exome

AF:

0.00245

Gnomad OTH exome

AF:

0.00260

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0681

AC:

71351

AN:

1047294

Hom.:

Cov.:

AF XY:

0.0670

AC XY:

35262

AN XY:

526586

show subpopulations

Gnomad4 AFR exome

AF:

0.0236

Gnomad4 AMR exome

AF:

0.116

Gnomad4 ASJ exome

AF:

0.0610

Gnomad4 EAS exome

AF:

0.0445

Gnomad4 SAS exome

AF:

0.0358

Gnomad4 FIN exome

AF:

0.0239

Gnomad4 NFE exome

AF:

0.0753

Gnomad4 OTH exome

AF:

0.0540

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0254

AC:

3255

AN:

128314

Hom.:

Cov.:

AF XY:

0.0267

AC XY:

1677

AN XY:

62920

show subpopulations

Gnomad4 AFR

AF:

0.0145

Gnomad4 AMR

AF:

0.0334

Gnomad4 ASJ

AF:

0.0325

Gnomad4 EAS

AF:

0.0296

Gnomad4 SAS

AF:

0.0228

Gnomad4 FIN

AF:

0.0249

Gnomad4 NFE

AF:

0.0300

Gnomad4 OTH

AF:

0.0280

Alfa

AF:

0.0289

Hom.:

ExAC

AF:

0.0572

AC:

6940

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

FAM136A-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

3.0

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.4

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.87

MPC

0.41

ClinPred

0.026

GERP RS

5.0

Varity_R

0.88

gMVP

0.75

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