8-144464837-G-C

Position:

• chr8-144464837-G-C

Variant summary

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

The NM_138496.3(TMEM276-ZFTRAF1):​c.65C>G​(p.Ser22Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TMEM276-ZFTRAF1 NM_138496.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM276-ZFTRAF1	NM_001408008.1	c.65C>G	p.Ser22Cys	missense_variant	2/6		NP_001394937.1
TMEM276-ZFTRAF1	NM_001408009.1	c.65C>G	p.Ser22Cys	missense_variant	2/6		NP_001394938.1
TMEM276-ZFTRAF1	NM_001408010.1	c.65C>G	p.Ser22Cys	missense_variant	2/6		NP_001394939.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000291316	ENST00000438911.6	c.65C>G	p.Ser22Cys	missense_variant	1/5	2		ENSP00000387426.2
TMEM276	ENST00000306145.10	c.65C>G	p.Ser22Cys	missense_variant	2/3	1		ENSP00000304826.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460536 Hom.: 0 Cov.: 38 AF XY: 0.00000963 AC XY: 7 AN XY: 726572

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

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

Aug 17, 2022

The c.65C>G (p.S22C) alteration is located in exon 1 (coding exon 1) of the CYHR1 gene. This alteration results from a C to G substitution at nucleotide position 65, causing the serine (S) at amino acid position 22 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	0.085
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T;T;.;.;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T;.;.;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.97	L;.;L;L;L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;D
REVEL	Benign	0.18
Sift	Uncertain	0.026	D;T;T;T;T;T;D
Sift4G	Benign	0.13	T;.;T;T;T;.;.
Polyphen		0.99	D;.;D;D;D;.;.
Vest4		0.52
MutPred		0.48		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);
MVP		0.85
MPC		0.39
ClinPred		0.92	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16

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: rs1192803561; hg19: chr8-145690220;