11-9287776-T-C

Variant names:

• chr11-9287776-T-C
• rs1852868329
• NM_015012.4:c.493A>G

Variant summary

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

The NM_015012.4(TMEM41B):​c.493A>G​(p.Met165Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM41B NM_015012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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]

ACMG classification

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	c.493A>G	p.Met165Val	missense_variant	Exon 5 of 7	ENST00000528080.6	NP_055827.1
TMEM41B	XM_047426969.1	c.500A>G	p.Tyr167Cys	missense_variant	Exon 5 of 6		XP_047282925.1
TMEM41B	NR_028491.3	n.645A>G		non_coding_transcript_exon_variant	Exon 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM41B	ENST00000528080.6	c.493A>G	p.Met165Val	missense_variant	Exon 5 of 7	1	NM_015012.4	ENSP00000433126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461068 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493A>G (p.M165V) alteration is located in exon 5 (coding exon 5) of the TMEM41B gene. This alteration results from a A to G substitution at nucleotide position 493, causing the methionine (M) at amino acid position 165 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	0.20
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.011	T;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.053
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	.;N;N
REVEL	Benign	0.19
Sift	Benign	0.033	.;D;D
Sift4G	Uncertain	0.033	D;D;T
Polyphen		0.018	B;B;.
Vest4		0.76
MutPred		0.45		Gain of catalytic residue at M165 (P = 0.0815);Gain of catalytic residue at M165 (P = 0.0815);Gain of catalytic residue at M165 (P = 0.0815);
MVP		0.56
MPC		0.28
ClinPred		0.87	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.88

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

Other links and lift over

dbSNP: rs1852868329; hg19: chr11-9309323;