Genetic Variant TMEM191B:p.Pro231Leu (chr22-18529694-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001242313.1(TMEM191B):c.692C>T(p.Pro231Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.00032 ( 1 hom., cov: 4)

Exomes 𝑓: 0.000096 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

TMEM191B
NM_001242313.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.109

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012826443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM191B	NM_001242313.1 link	c.692C>T	p.Pro231Leu	missense_variant	Exon 6 of 9	ENST00000612978.5	NP_001229242.1	P0C7N4
TMEM191B	XM_011546160.4 link	c.663+29C>T		intron_variant	Intron 6 of 9		XP_011544462.1
TMEM191B	XR_951236.3 link	n.842+29C>T		intron_variant	Intron 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM191B	ENST00000612978.5 link	c.692C>T	p.Pro231Leu	missense_variant	Exon 6 of 9	5	NM_001242313.1	ENSP00000481358.1		P0C7N4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

40172

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00375

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:

0.000897

AC:

AN:

30116

Hom.:

AF XY:

0.000898

AC XY:

AN XY:

15596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00441

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:

0.00192

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000963

AC:

AN:

404998

Hom.:

Cov.:

AF XY:

0.0000995

AC XY:

AN XY:

211038

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00242

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:

0.0000877

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000324

AC:

AN:

40172

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

AN XY:

18342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00375

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

Alfa

AF:

0.000169

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.692C>T (p.P231L) alteration is located in exon 6 (coding exon 6) of the TMEM191B gene. This alteration results from a C to T substitution at nucleotide position 692, causing the proline (P) at amino acid position 231 to be replaced by a leucine (L). 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

0.092

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.011

FATHMM_MKL

Benign

0.0042

LIST_S2

Benign

0.48

MetaRNN

Benign

0.013

PrimateAI

Uncertain

0.62

Sift4G

Benign

0.24

Vest4

0.17

MVP

0.40

GERP RS

-0.43

Varity_R

0.031

gMVP

0.031

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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