X-66164321-C-T

Variant names:

• chrX-66164321-C-T
• rs1028348
• NM_001367233.3:c.-163C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001367233.3(HEPH):​c.-163C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 750,884 control chromosomes in the GnomAD database, including 9,497 homozygotes. There are 31,242 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: 𝑓 0.25 (4639 hom., 7616 hem., cov: 22)
  • Exomes 𝑓: 0.12 (4858 hom. 23626 hem.)
• Consequence: HEPH NM_001367233.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.221
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367233.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPH	NM_001367233.3	MANE Select	c.-163C>T		5_prime_UTR	Exon 1 of 21	NP_001354162.2
	HEPH	NR_159800.1		n.75C>T		non_coding_transcript_exon	Exon 1 of 20
	HEPH	NR_159801.2		n.75C>T		non_coding_transcript_exon	Exon 1 of 22

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPH	ENST00000343002.7	TSL:1 MANE Select	c.-163C>T		5_prime_UTR	Exon 1 of 21	ENSP00000343939.2
	HEPH	ENST00000336279.9	TSL:1	c.-784C>T		5_prime_UTR	Exon 1 of 20	ENSP00000337418.5
	HEPH	ENST00000519389.6	TSL:1	c.-14+1445C>T		intron	N/A	ENSP00000430620.2

Frequencies

GnomAD3 genomes AF: 0.251 AC: 27671 AN: 110460 Hom.: 4639 Cov.: 22

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.00140

Gnomad SAS AF: 0.0793

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0711

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.190

GnomAD4 exome AF: 0.125 AC: 79890 AN: 640371 Hom.: 4858 Cov.: 22 AF XY: 0.123 AC XY: 23626 AN XY: 192033

African (AFR) AF: 0.646 AC: 8012 AN: 12396

American (AMR) AF: 0.200 AC: 163 AN: 817

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 554 AN: 3971

East Asian (EAS) AF: 0.00 AC: 0 AN: 3025

South Asian (SAS) AF: 0.0985 AC: 1182 AN: 11995

European-Finnish (FIN) AF: 0.143 AC: 38 AN: 265

Middle Eastern (MID) AF: 0.122 AC: 135 AN: 1103

European-Non Finnish (NFE) AF: 0.114 AC: 67024 AN: 585638

Other (OTH) AF: 0.131 AC: 2782 AN: 21161

GnomAD4 genome AF: 0.251 AC: 27717 AN: 110513 Hom.: 4639 Cov.: 22 AF XY: 0.232 AC XY: 7616 AN XY: 32791

African (AFR) AF: 0.612 AC: 18421 AN: 30110

American (AMR) AF: 0.174 AC: 1808 AN: 10417

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 406 AN: 2641

East Asian (EAS) AF: 0.00141 AC: 5 AN: 3557

South Asian (SAS) AF: 0.0803 AC: 208 AN: 2590

European-Finnish (FIN) AF: 0.119 AC: 703 AN: 5884

Middle Eastern (MID) AF: 0.0780 AC: 17 AN: 218

European-Non Finnish (NFE) AF: 0.109 AC: 5779 AN: 52914

Other (OTH) AF: 0.190 AC: 285 AN: 1503

Alfa AF: 0.151 Hom.: 13000

Bravo AF: 0.273

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.2
DANN	Benign	0.69
PhyloP100		0.22
PromoterAI		0.015	Neutral
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1028348; hg19: chrX-65384163;