X-66162843-T-G

Variant names:

• chrX-66162843-T-G
• rs5919015
• ENST00000519389.6:c.-47T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000519389.6(HEPH):​c.-47T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000959 in 1,042,657 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.6e-7 (0 hom. 1 hem.)
• Consequence: HEPH ENST00000519389.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.179
• Publications: 0 publications found

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]

HEPH Gene-Disease associations (from GenCC):

• hereditary hemochromatosis

  Inheritance: XL Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07718024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEPH	XM_011531073.4	c.116T>G	p.Val39Gly	missense_variant	Exon 1 of 21		XP_011529375.1
HEPH	XM_047442694.1	c.79T>G	p.Cys27Gly	missense_variant	Exon 1 of 21		XP_047298650.1
HEPH	XM_011531074.3	c.116T>G	p.Val39Gly	missense_variant	Exon 1 of 20		XP_011529376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEPH	ENST00000519389.6	c.-47T>G		5_prime_UTR_variant	Exon 1 of 21	1		ENSP00000430620.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.59e-7 AC: 1 AN: 1042657 Hom.: 0 Cov.: 34 AF XY: 0.00000293 AC XY: 1 AN XY: 341143

African (AFR) AF: 0.00 AC: 0 AN: 24891

American (AMR) AF: 0.00 AC: 0 AN: 27871

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18632

East Asian (EAS) AF: 0.00 AC: 0 AN: 27127

South Asian (SAS) AF: 0.00 AC: 0 AN: 49846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4083

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 819173

Other (OTH) AF: 0.00 AC: 0 AN: 44302

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.4
DANN	Benign	0.80
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.099	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.077	T
MetaSVM	Uncertain	0.41	D
PhyloP100		-0.18
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.17
Sift	Uncertain	0.029	D
Sift4G	Benign	0.097	T
Vest4		0.082
MutPred		0.49		Gain of disorder (P = 0.0092);
MVP		0.32
MPC		0.10
ClinPred		0.062	T
GERP RS		-4.4
PromoterAI		-0.018	Neutral
gMVP		0.46
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs5919015; hg19: chrX-65382685;