dbSNP rs112790117: FAM136A:p.Arg91Cys (chr2-70301741-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001329752.2(FAM136A):c.271C>T(p.Arg91Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,539,414 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.014 ( 63 hom., cov: 34)

Exomes 𝑓: 0.0014 ( 46 hom. )

Consequence

FAM136A
NM_001329752.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0820

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Meniere disease
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

FAM136A links:

ENSG00000233849 (HGNC:):

ENSG00000233849 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002407968).

BP6

Variant 2-70301741-G-A is Benign according to our data. Variant chr2-70301741-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056074.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0138 (2098/152346) while in subpopulation AFR AF = 0.0477 (1983/41574). AF 95% confidence interval is 0.0459. There are 63 homozygotes in GnomAd4. There are 1031 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 63 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329752.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM136A	NM_001329752.2	MANE Select	c.271C>T	p.Arg91Cys	missense	Exon 1 of 3	NP_001316681.1	E7EQY1
FAM136A	NM_001329753.2		c.271C>T	p.Arg91Cys	missense	Exon 1 of 3	NP_001316682.1
FAM136A	NM_032822.3		c.87+184C>T		intron	N/A	NP_116211.2	Q96C01

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM136A	ENST00000430566.6	TSL:3 MANE Select	c.271C>T	p.Arg91Cys	missense	Exon 1 of 3	ENSP00000397269.1	E7EQY1
FAM136A	ENST00000037869.8	TSL:1	c.87+184C>T		intron	N/A	ENSP00000037869.3	Q96C01
FAM136A	ENST00000460307.1	TSL:1	n.133-138C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2091

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0477

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00315

AC:

435

AN:

138030

AF XY:

0.00233

show subpopulations

Gnomad AFR exome

AF:

0.0516

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000276

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000954

Gnomad OTH exome

AF:

0.00120

GnomAD4 exome

AF:

0.00144

AC:

2000

AN:

1387068

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

861

AN XY:

684382

show subpopulations

African (AFR)

AF:

0.0512

AC:

1615

AN:

31560

American (AMR)

AF:

0.00370

AC:

132

AN:

35658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25156

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35712

South Asian (SAS)

AF:

0.000126

AC:

AN:

79186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37876

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000389

AC:

AN:

1078358

Other (OTH)

AF:

0.00334

AC:

193

AN:

57868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0138

AC:

2098

AN:

152346

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1031

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0477

AC:

1983

AN:

41574

American (AMR)

AF:

0.00529

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

107

214

320

427

534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0241

Hom.:

Bravo

AF:

0.0167

ExAC

AF:

0.00275

AC:

101

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

FAM136A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Benign

8.9

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

PhyloP100

-0.082

PROVEAN

Benign

-0.83

REVEL

Benign

0.042

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0030

Vest4

0.24

MVP

0.030

ClinPred

0.017

GERP RS

1.7

PromoterAI

-0.031

Neutral

(source)

gMVP

0.074

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over