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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM191B	NM_001242313.1 link	c.344C>T	p.Ala115Val	missense_variant	Exon 2 of 9	ENST00000612978.5	NP_001229242.1	P0C7N4
TMEM191B	XM_011546160.4 link	c.344C>T	p.Ala115Val	missense_variant	Exon 2 of 10		XP_011544462.1
TMEM191B	XR_951236.3 link	n.523C>T		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM191B	ENST00000612978.5 link	c.344C>T	p.Ala115Val	missense_variant	Exon 2 of 9	5	NM_001242313.1	ENSP00000481358.1	P0C7N4
TMEM191B	ENST00000613577.5 link	c.344C>T	p.Ala115Val	missense_variant	Exon 2 of 10	3		ENSP00000483146.2	A0A087X073
TMEM191B	ENST00000614395.4 link	n.523C>T		non_coding_transcript_exon_variant	Exon 2 of 5	2

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

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1220232

Hom.:

Cov.:

AF XY:

0.0000264

AC XY:

AN XY:

606108

show subpopulations

Gnomad4 AFR exome

AF:

0.0000717

Gnomad4 AMR exome

AF:

0.0000749

Gnomad4 ASJ exome

AF:

0.0000436

Gnomad4 EAS exome

AF:

0.0000599

Gnomad4 SAS exome

AF:

0.0000292

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000115

Gnomad4 OTH exome

AF:

0.0000194

GnomAD4 genome

AF:

0.0000313

AC:

AN:

127880

Hom.:

Cov.:

AF XY:

0.0000327

AC XY:

AN XY:

61158

show subpopulations

Gnomad4 AFR

AF:

0.0000292

Gnomad4 AMR

AF:

0.000176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.344C>T (p.A115V) alteration is located in exon 2 (coding exon 2) of the TMEM191B gene. This alteration results from a C to T substitution at nucleotide position 344, causing the alanine (A) at amino acid position 115 to be replaced by a valine (V). 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

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.013

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.56

MetaRNN

Benign

0.096

PrimateAI

Pathogenic

0.82

Sift4G

Benign

0.45

Vest4

0.087

MVP

0.18

GERP RS

0.43

Varity_R

0.038

gMVP

0.019

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

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