Genetic Variant TMEM41B:p.Asp91Gly (chr11-9295355-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015012.4(TMEM41B):c.272A>G(p.Asp91Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,442,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TMEM41B
NM_015012.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM41B	NM_015012.4 link	c.272A>G	p.Asp91Gly	missense_variant	Exon 3 of 7	ENST00000528080.6	NP_055827.1	Q5BJD5-1
TMEM41B	NM_001165030.3 link	c.272A>G	p.Asp91Gly	missense_variant	Exon 3 of 3		NP_001158502.1	Q5BJD5-3
TMEM41B	XM_047426969.1 link	c.272A>G	p.Asp91Gly	missense_variant	Exon 3 of 6		XP_047282925.1
TMEM41B	NR_028491.3 link	n.424A>G		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.272A>G	p.Asp91Gly	missense_variant	Exon 3 of 7	1	NM_015012.4	ENSP00000433126.1		Q5BJD5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1442770

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717512

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000393

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.272A>G (p.D91G) alteration is located in exon 3 (coding exon 3) of the TMEM41B gene. This alteration results from a A to G substitution at nucleotide position 272, causing the aspartic acid (D) at amino acid position 91 to be replaced by a glycine (G). 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

0.57

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

T;T;T;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;D;D

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.7

L;L;.;L

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.4

.;D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.026

.;D;D;D

Sift4G

Uncertain

0.054

T;T;T;D

Polyphen

0.90

P;P;.;.

Vest4

0.86

MutPred

0.41

Loss of stability (P = 0.0175);Loss of stability (P = 0.0175);Loss of stability (P = 0.0175);Loss of stability (P = 0.0175);

MVP

0.93

MPC

0.32

ClinPred

0.98

GERP RS

5.5

Varity_R

0.45

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.43

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over