rs708969

Variant names:

• chrX-66250053-A-T
• rs708969
• NM_001367233.3:c.2564-4982A>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.2564-4982A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 110,332 control chromosomes in the GnomAD database, including 3,963 homozygotes. There are 8,443 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 0.27 (3963 hom., 8443 hem., cov: 22)
• Consequence: HEPH NM_001367233.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.387
• Publications: 4 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEPH	NM_001367233.3	c.2564-4982A>T		intron_variant	Intron 15 of 20	ENST00000343002.7	NP_001354162.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEPH	ENST00000343002.7	c.2564-4982A>T		intron_variant	Intron 15 of 20	1	NM_001367233.3	ENSP00000343939.2

Frequencies

GnomAD3 genomes AF: 0.274 AC: 30179 AN: 110280 Hom.: 3962 Cov.: 22

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.0870

Gnomad EAS AF: 0.00113

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.234

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.274 AC: 30215 AN: 110332 Hom.: 3963 Cov.: 22 AF XY: 0.259 AC XY: 8443 AN XY: 32652

African (AFR) AF: 0.509 AC: 15378 AN: 30238

American (AMR) AF: 0.214 AC: 2222 AN: 10401

Ashkenazi Jewish (ASJ) AF: 0.0870 AC: 229 AN: 2632

East Asian (EAS) AF: 0.00113 AC: 4 AN: 3532

South Asian (SAS) AF: 0.0866 AC: 224 AN: 2586

European-Finnish (FIN) AF: 0.234 AC: 1373 AN: 5874

Middle Eastern (MID) AF: 0.185 AC: 40 AN: 216

European-Non Finnish (NFE) AF: 0.196 AC: 10306 AN: 52677

Other (OTH) AF: 0.232 AC: 348 AN: 1497

Alfa AF: 0.241 Hom.: 1675

Bravo AF: 0.285

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.38
DANN	Benign	0.62
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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: rs708969; hg19: chrX-65469895;