Variant chr8-144464609-T-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_138496.3(TMEM276-ZFTRAF1):c.97A>T(p.Ser33Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,605,906 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

TMEM276-ZFTRAF1
NM_138496.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

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:

Genome browser will be placed here

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=0.07360527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein
TMEM276-ZFTRAF1	NM_001408008.1 link	c.97A>T	p.Ser33Cys	missense_variant	3/6	NP_001394937.1
TMEM276-ZFTRAF1	NM_001408009.1 link	c.97A>T	p.Ser33Cys	missense_variant	3/6	NP_001394938.1
TMEM276-ZFTRAF1	NM_001408010.1 link	c.97A>T	p.Ser33Cys	missense_variant	3/6	NP_001394939.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000291316	ENST00000438911.6 link	c.97A>T	p.Ser33Cys	missense_variant	2/5	2		ENSP00000387426.2
TMEM276	ENST00000306145.10 link	c.97A>T	p.Ser33Cys	missense_variant	3/3	1		ENSP00000304826.5		P0DTL5

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000283

AC:

AN:

240594

Hom.:

AF XY:

0.000312

AC XY:

AN XY:

131292

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000602

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000611

AC:

888

AN:

1453624

Hom.:

Cov.:

AF XY:

0.000614

AC XY:

444

AN XY:

722708

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.0000226

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:

0.000783

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.000407

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000517

Hom.:

Bravo

AF:

0.000412

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.97A>T (p.S33C) alteration is located in exon 2 (coding exon 2) of the CYHR1 gene. This alteration results from a A to T substitution at nucleotide position 97, causing the serine (S) at amino acid position 33 to be replaced by a cysteine (C). 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

0.099

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Pathogenic

DANN

Benign

0.94

DEOGEN2

Benign

0.059

T;.;.;.;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.62

T;.;.;T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.074

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;N;N;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.4

N;D;D;D;D;D

REVEL

Benign

0.066

Sift

Benign

0.047

D;T;T;T;D;D

Sift4G

Uncertain

0.019

D;T;T;T;.;.

Polyphen

0.66

P;D;D;D;.;.

Vest4

0.27

MVP

0.54

MPC

0.10

ClinPred

0.064

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.098

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

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