dbSNP rs1824542926: ENSG00000291316:p.Val27Leu (chr8-144464823-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138496.3(TMEM276-ZFTRAF1):c.79G>C(p.Val27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V27M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM276-ZFTRAF1
NM_138496.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.137

Variant links:

Genes affected

ENSG00000291316 (HGNC:56752): (TMEM276-ZFTRAF1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring LOC84773 and cysteine and histidine rich 1 (CYHR1). It encodes a fusion protein that shares sequence identity with proteins encoded by both independent genes. [provided by RefSeq, Feb 2022]

ENSG00000291316 links:

TMEM276 (HGNC:56235): (transmembrane protein 276)

TMEM276 links:

ENSG00000254578 (HGNC:):

ENSG00000254578 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05426222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
TMEM276-ZFTRAF1	NM_001408008.1 link	c.79G>C	p.Val27Leu	missense_variant	Exon 2 of 6	NP_001394937.1
TMEM276-ZFTRAF1	NM_001408009.1 link	c.79G>C	p.Val27Leu	missense_variant	Exon 2 of 6	NP_001394938.1
TMEM276-ZFTRAF1	NM_001408010.1 link	c.79G>C	p.Val27Leu	missense_variant	Exon 2 of 6	NP_001394939.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000291316	ENST00000438911.6 link	c.79G>C	p.Val27Leu	missense_variant	Exon 1 of 5	2		ENSP00000387426.2
TMEM276	ENST00000306145.10 link	c.79G>C	p.Val27Leu	missense_variant	Exon 2 of 3	1		ENSP00000304826.5		P0DTL5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460442

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726508

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.025

T;T;.;.;.;.;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.68

T;T;.;.;T;T;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.054

T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.46

N;.;N;N;N;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.15

N;N;N;N;N;N;N

REVEL

Benign

0.024

Sift

Uncertain

0.014

D;T;T;T;T;T;T

Sift4G

Benign

0.19

T;.;T;T;T;.;.

Polyphen

0.0

B;.;B;B;B;.;.

Vest4

0.066

MutPred

0.25

Loss of catalytic residue at V27 (P = 0.074);Loss of catalytic residue at V27 (P = 0.074);Loss of catalytic residue at V27 (P = 0.074);Loss of catalytic residue at V27 (P = 0.074);Loss of catalytic residue at V27 (P = 0.074);Loss of catalytic residue at V27 (P = 0.074);Loss of catalytic residue at V27 (P = 0.074);

MVP

0.44

MPC

0.080

ClinPred

0.095

GERP RS

1.5

Varity_R

0.074

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over