8-144464814-C-T

Position:

• chr8-144464814-C-T

Variant summary

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

The NM_138496.3(TMEM276-ZFTRAF1):​c.88G>A​(p.Ala30Thr) 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. 14/20 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 NM_138496.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.833

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]

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

ENSG00000254578 (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=0.14030284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM276-ZFTRAF1	NM_001408008.1	c.88G>A	p.Ala30Thr	missense_variant	2/6		NP_001394937.1
TMEM276-ZFTRAF1	NM_001408009.1	c.88G>A	p.Ala30Thr	missense_variant	2/6		NP_001394938.1
TMEM276-ZFTRAF1	NM_001408010.1	c.88G>A	p.Ala30Thr	missense_variant	2/6		NP_001394939.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000291316	ENST00000438911.6	c.88G>A	p.Ala30Thr	missense_variant	1/5	2		ENSP00000387426.2
TMEM276	ENST00000306145.10	c.88G>A	p.Ala30Thr	missense_variant	2/3	1		ENSP00000304826.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 38

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 10, 2022

The c.88G>A (p.A30T) 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 88, causing the alanine (A) at amino acid position 30 to be replaced by a threonine (T). 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	0.085
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T;T;.;.;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.69	T;T;.;.;T;T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.46	N;.;N;N;N;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.22	N;N;N;N;N;N;D
REVEL	Benign	0.018
Sift	Benign	0.64	T;T;T;T;T;T;D
Sift4G	Benign	0.73	T;.;T;T;T;.;.
Polyphen		0.0	B;.;B;B;B;.;.
Vest4		0.12
MutPred		0.20		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.70
MPC		0.079
ClinPred		0.76	D
GERP RS		3.5
Varity_R		0.086

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.

Other links and lift over

hg19: chr8-145690197;