X-66162755-A-T

Position:

• chrX-66162755-A-T

Variant summary

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

The NM_138737.6(HEPH):​c.-135A>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HEPH NM_138737.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

Genes affected

HEPH (HGNC:4866): (hephaestin) This gene encodes a member of the multicopper oxidase protein family. The encoded protein is involved in the transport of dietary iron from epithelial cells of the intestinal lumen into the circulatory system, and may be involved in copper transport and homeostasis. In mouse, defects in this gene can lead to severe microcytic anemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

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=0.11657426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEPH	NM_138737.6	c.-135A>T		5_prime_UTR_premature_start_codon_gain_variant	1/21		NP_620074.4
HEPH	XM_047442694.1	c.-10A>T		5_prime_UTR_premature_start_codon_gain_variant	1/21		XP_047298650.1
HEPH	XM_047442695.1	c.-1328A>T		5_prime_UTR_premature_start_codon_gain_variant	1/22		XP_047298651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEPH	ENST00000519389.6	c.-135A>T		5_prime_UTR_premature_start_codon_gain_variant	1/21	1		ENSP00000430620.2
HEPH	ENST00000519389.6	c.-135A>T		5_prime_UTR_variant	1/21	1		ENSP00000430620.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

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

Sep 14, 2022

The c.28A>T (p.S10C) alteration is located in exon 1 (coding exon 1) of the HEPH gene. This alteration results from a A to T substitution at nucleotide position 28, causing the serine (S) at amino acid position 10 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
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	12
DANN	Benign	0.94
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.35	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.57	D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.15	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Vest4		0.18
MutPred		0.34		Gain of catalytic residue at L11 (P = 0.0107);
MVP		0.28
MPC		0.090
ClinPred		0.080	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.21

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: chrX-65382597;