X-66170607-A-G

Position:

• chrX-66170607-A-G

Variant summary

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

The NM_001367233.3(HEPH):​c.37A>G​(p.Met13Val) 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: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: HEPH NM_001367233.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.144

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=0.08757284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEPH	NM_001367233.3	c.37A>G	p.Met13Val	missense_variant	2/21	ENST00000343002.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEPH	ENST00000343002.7	c.37A>G	p.Met13Val	missense_variant	2/21	1	NM_001367233.3	P5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097437 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362865

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

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

Oct 20, 2023

The c.199A>G (p.M67V) alteration is located in exon 2 (coding exon 2) of the HEPH gene. This alteration results from a A to G substitution at nucleotide position 199, causing the methionine (M) at amino acid position 67 to be replaced by a valine (V). 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	0.073
BayesDel_addAF	Benign	0.0050	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.093
DANN	Benign	0.34
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.57	T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.088	T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	0.99	D;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.10	N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.53	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;B;.
Vest4		0.10
MutPred		0.32		.;Loss of loop (P = 0.0374);.;.;Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);
MVP		0.66
MPC		0.081
ClinPred		0.027	T
GERP RS		-3.9
Varity_R		0.065
gMVP		0.38

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-65390449;