Genetic Variant TMEM191B:p.Ala115Val (chr22-18528606-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001242313.1(TMEM191B):c.344C>T(p.Ala115Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,348,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000031 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

TMEM191B
NM_001242313.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.349

Publications

0 publications found

Variant links:

Genes affected

TMEM191B (HGNC:33600): (transmembrane protein 191B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM191B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09598529).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242313.1. 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
	TMEM191B	NM_001242313.1	MANE Select	c.344C>T	p.Ala115Val	missense	Exon 2 of 9	NP_001229242.1	P0C7N4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM191B	ENST00000612978.5	TSL:5 MANE Select	c.344C>T	p.Ala115Val	missense	Exon 2 of 9	ENSP00000481358.1	P0C7N4
TMEM191B	ENST00000613577.5	TSL:3	c.344C>T	p.Ala115Val	missense	Exon 2 of 10	ENSP00000483146.2	A0A087X073
TMEM191B	ENST00000614395.4	TSL:2	n.523C>T		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000313

AC:

AN:

127880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000176

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:

0.0000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000350

AC:

AN:

85760

AF XY:

0.0000649

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.000355

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1220232

Hom.:

Cov.:

AF XY:

0.0000264

AC XY:

AN XY:

606108

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000717

AC:

AN:

27896

American (AMR)

AF:

0.0000749

AC:

AN:

26716

Ashkenazi Jewish (ASJ)

AF:

0.0000436

AC:

AN:

22928

East Asian (EAS)

AF:

0.0000599

AC:

AN:

33378

South Asian (SAS)

AF:

0.0000292

AC:

AN:

68414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3762

European-Non Finnish (NFE)

AF:

0.0000115

AC:

AN:

952896

Other (OTH)

AF:

0.0000194

AC:

AN:

51556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000180511), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.382

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000313

AC:

AN:

127880

Hom.:

Cov.:

AF XY:

0.0000327

AC XY:

AN XY:

61158

show subpopulations

African (AFR)

AF:

0.0000292

AC:

AN:

34276

American (AMR)

AF:

0.000176

AC:

AN:

11380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3270

East Asian (EAS)

AF:

0.00

AC:

AN:

3342

South Asian (SAS)

AF:

0.00

AC:

AN:

3132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

61914

Other (OTH)

AF:

0.00

AC:

AN:

1692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000843

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.013

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.56

MetaRNN

Benign

0.096

PhyloP100

-0.35

PrimateAI

Pathogenic

0.82

Sift4G

Benign

0.45

Vest4

0.087

MVP

0.18

GERP RS

0.43

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.038

gMVP

0.019

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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