chrX-66173775-T-C

Position:

• chrX-66173775-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001367233.3(HEPH):​c.599T>C​(p.Ile200Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000831 in 1,083,680 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000083 (0 hom. 5 hem.)
• Consequence: HEPH NM_001367233.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• BS2: High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEPH	NM_001367233.3	c.599T>C	p.Ile200Thr	missense_variant	4/21	ENST00000343002.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEPH	ENST00000343002.7	c.599T>C	p.Ile200Thr	missense_variant	4/21	1	NM_001367233.3	P5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000831 AC: 9 AN: 1083680 Hom.: 0 Cov.: 30 AF XY: 0.0000142 AC XY: 5 AN XY: 352122

Gnomad4 AFR exome AF: 0.000115

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000439

GnomAD4 genome Cov.: 22

Alfa AF: 0.000102 Hom.: 1

ExAC AF: 0.0000166 AC: 2

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 27, 2021

The c.761T>C (p.I254T) alteration is located in exon 4 (coding exon 4) of the HEPH gene. This alteration results from a T to C substitution at nucleotide position 761, causing the isoleucine (I) at amino acid position 254 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	0.18
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.83	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Benign	0.036	D;D;D;T;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;D;D;.
Vest4		0.75
MutPred		0.67		.;Loss of catalytic residue at P202 (P = 0.0452);.;.;Loss of catalytic residue at P202 (P = 0.0452);Loss of catalytic residue at P202 (P = 0.0452);
MVP		0.56
MPC		0.39
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.96

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: rs746718981; hg19: chrX-65393617;