Genetic Variant TMEM41B:p.Ala116Val (chr11-9295280-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015012.4(TMEM41B):c.347C>T(p.Ala116Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000035 in 1,571,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A116T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TMEM41B
NM_015012.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.95

Variant links:

Genes affected

TMEM41B (HGNC:28948): (transmembrane protein 41B) Involved in autophagosome assembly. Located in endoplasmic reticulum membrane and mitochondria-associated endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM41B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM41B	NM_015012.4 link	c.347C>T	p.Ala116Val	missense_variant	Exon 3 of 7	ENST00000528080.6	NP_055827.1	Q5BJD5-1
TMEM41B	NM_001165030.3 link	c.347C>T	p.Ala116Val	missense_variant	Exon 3 of 3		NP_001158502.1	Q5BJD5-3
TMEM41B	XM_047426969.1 link	c.347C>T	p.Ala116Val	missense_variant	Exon 3 of 6		XP_047282925.1
TMEM41B	NR_028491.3 link	n.499C>T		non_coding_transcript_exon_variant	Exon 3 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM41B	ENST00000528080.6 link	c.347C>T	p.Ala116Val	missense_variant	Exon 3 of 7	1	NM_015012.4	ENSP00000433126.1		Q5BJD5-1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000454

AC:

AN:

220394

Hom.:

AF XY:

0.0000420

AC XY:

AN XY:

119032

show subpopulations

Gnomad AFR exome

AF:

0.000634

Gnomad AMR exome

AF:

0.00

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:

0.0000101

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000148

AC:

AN:

1419764

Hom.:

Cov.:

AF XY:

0.00000567

AC XY:

AN XY:

706050

show subpopulations

Gnomad4 AFR exome

AF:

0.000465

Gnomad4 AMR exome

AF:

0.0000506

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:

0.0000682

GnomAD4 genome

AF:

0.000223

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000724

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.000246

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.347C>T (p.A116V) alteration is located in exon 3 (coding exon 3) of the TMEM41B gene. This alteration results from a C to T substitution at nucleotide position 347, causing the alanine (A) at amino acid position 116 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

Pathogenic

0.86

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

T;T;T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.1

M;M;.;M

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.7

.;D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.011

.;D;D;D

Sift4G

Benign

0.13

T;T;T;D

Polyphen

0.82

P;P;.;.

Vest4

0.78

MVP

0.63

MPC

0.58

ClinPred

0.28

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.43

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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