Genetic Variant TMEM35B:p.Val32Ala (chr1-34985211-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001195156.2(TMEM35B):c.95T>C(p.Val32Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000866 in 1,385,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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: 0.0000087 ( 0 hom. )

Consequence

TMEM35B
NM_001195156.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.129

Variant links:

Genes affected

TMEM35B (HGNC:40021): (transmembrane protein 35B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM35B links:

ENSG00000284773 (HGNC:):

ENSG00000284773 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07157585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM35B	NM_001195156.2 link	c.95T>C	p.Val32Ala	missense_variant	Exon 1 of 3	ENST00000373337.4	NP_001182085.1	Q8NCS4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM35B	ENST00000373337.4 link	c.95T>C	p.Val32Ala	missense_variant	Exon 1 of 3	1	NM_001195156.2	ENSP00000362435.3	Q8NCS4
ENSG00000284773	ENST00000417456.1 link	c.95T>C	p.Val32Ala	missense_variant	Exon 1 of 2	2		ENSP00000493999.1	A0A2R8YCV2
ENSG00000271741	ENST00000487874.1 link	n.2147-1264T>C		intron_variant	Intron 15 of 16	5		ENSP00000421752.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000866

AC:

AN:

1385870

Hom.:

Cov.:

AF XY:

0.00000878

AC XY:

AN XY:

683584

show subpopulations

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:

0.0000102

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.95T>C (p.V32A) alteration is located in exon 1 (coding exon 1) of the TMEM35B gene. This alteration results from a T to C substitution at nucleotide position 95, causing the valine (V) at amino acid position 32 to be replaced by an alanine (A). 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

0.094

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

5.5

DANN

Benign

0.65

DEOGEN2

Benign

0.015

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.30

T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.072

T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.3

.;N

REVEL

Benign

0.023

Sift

Benign

0.33

.;T

Sift4G

Benign

0.20

.;T

Polyphen

0.0060

.;B

Vest4

0.039

MutPred

0.35

Gain of disorder (P = 0.0283);Gain of disorder (P = 0.0283);

MVP

0.014

ClinPred

0.063

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.041

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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