8-144453385-C-T

Position:

• chr8-144453385-C-T

Variant summary

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

The NM_001330618.2(ZFTRAF1):​c.448G>A​(p.Ala150Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ZFTRAF1 NM_001330618.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

Genes affected

ZFTRAF1 (HGNC:17806): (zinc finger TRAF-type containing 1) Predicted to enable zinc ion binding activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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]

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
ZFTRAF1	NM_001330618.2	c.448G>A	p.Ala150Thr	missense_variant	2/4	ENST00000530374.6	NP_001317547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFTRAF1	ENST00000530374.6	c.448G>A	p.Ala150Thr	missense_variant	2/4	3	NM_001330618.2	ENSP00000433769.1
ENSG00000291316	ENST00000438911.6	c.322G>A	p.Ala108Thr	missense_variant	3/5	2		ENSP00000387426.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

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

Jul 16, 2024

The c.322G>A (p.A108T) alteration is located in exon 3 (coding exon 3) of the CYHR1 gene. This alteration results from a G to A substitution at nucleotide position 322, causing the alanine (A) at amino acid position 108 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.49
MutPred		0.29		Gain of methylation at K104 (P = 0.047);.;.;
MVP		0.73
MPC		0.43
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.50
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1824108874; hg19: chr8-145678768;