8-144464823-C-T

Position:

• chr8-144464823-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000438911.6(TMEM276-ZFTRAF1):​c.79G>A​(p.Val27Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 34)
• Consequence: TMEM276-ZFTRAF1 ENST00000438911.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.137

Genes affected

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

TMEM276-ZFTRAF1 (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]

(HGNC:):

ACMG classification

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=0.10142097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM276	NM_032687.4	c.79G>A	p.Val27Met	missense_variant	2/3	ENST00000306145.10	NP_116076.1
TMEM276-ZFTRAF1	NM_001408018.1	c.79G>A	p.Val27Met	missense_variant	2/5		NP_001394947.1
TMEM276	NM_001408062.1	c.79G>A	p.Val27Met	missense_variant	2/3		NP_001394991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM276	ENST00000306145.10	c.79G>A	p.Val27Met	missense_variant	2/3	1	NM_032687.4	ENSP00000304826	P1
TMEM276-ZFTRAF1	ENST00000438911.6	c.79G>A	p.Val27Met	missense_variant	1/5	2		ENSP00000387426	P1
	ENST00000525461.1	n.240-89C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.79G>A (p.V27M) alteration is located in exon 1 (coding exon 1) of the CYHR1 gene. This alteration results from a G to A substitution at nucleotide position 79, causing the valine (V) at amino acid position 27 to be replaced by a methionine (M). 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	0.17
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T;T;.;.;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.85	T;T;.;.;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.81	L;.;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.030	N;N;N;N;N;N;N
REVEL	Benign	0.068
Sift	Uncertain	0.0040	D;D;D;D;D;D;D
Sift4G	Uncertain	0.058	T;.;D;D;D;.;.
Polyphen		0.074	B;.;P;P;P;.;.
Vest4		0.25
MutPred		0.19		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP		0.57
MPC		0.091
ClinPred		0.45	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061

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

Other links and lift over

dbSNP: rs1824542926; hg19: chr8-145690206;