Genetic Variant TMEM41A:p.Pro3Ser (chr3-185498955-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_080652.4(TMEM41A):c.7C>T(p.Pro3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000691 in 1,446,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. P3L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

TMEM41A
NM_080652.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.40

Publications

0 publications found

Variant links:

Genes affected

TMEM41A (HGNC:30544): (transmembrane protein 41A) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM41A links:

ENSG00000286086 (HGNC:58335):

ENSG00000286086 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06694609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM41A	NM_080652.4 link	c.7C>T	p.Pro3Ser	missense_variant	Exon 1 of 5	ENST00000421852.6	NP_542383.1	Q96HV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM41A	ENST00000421852.6 link	c.7C>T	p.Pro3Ser	missense_variant	Exon 1 of 5	1	NM_080652.4	ENSP00000406885.1		Q96HV5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000691

AC:

AN:

1446312

Hom.:

Cov.:

AF XY:

0.00000974

AC XY:

AN XY:

718342

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32928

American (AMR)

AF:

0.00

AC:

AN:

42884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25748

East Asian (EAS)

AF:

0.00

AC:

AN:

38688

South Asian (SAS)

AF:

0.00

AC:

AN:

83996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

0.00000904

AC:

AN:

1105650

Other (OTH)

AF:

0.00

AC:

AN:

59678

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000146), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Sep 26, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7C>T (p.P3S) alteration is located in exon 1 (coding exon 1) of the TMEM41A gene. This alteration results from a C to T substitution at nucleotide position 7, causing the proline (P) at amino acid position 3 to be replaced by a serine (S). 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

0.083

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0049

T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.067

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.32

N;.

PhyloP100

2.4

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.16

Sift

Benign

0.87

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.12

MutPred

0.66

Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.040

MPC

0.21

ClinPred

0.11

GERP RS

2.4

PromoterAI

0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.28

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over