X-66243655-A-G

Variant names:

• chrX-66243655-A-G
• rs1068536
• NM_001367233.3:c.2564-11380A>G

Variant summary

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

The NM_001367233.3(HEPH):​c.2564-11380A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 112,121 control chromosomes in the GnomAD database, including 9,385 homozygotes. There are 12,552 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 0.38 (9385 hom., 12552 hem., cov: 25)
• Consequence: HEPH NM_001367233.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 2 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEPH	NM_001367233.3	c.2564-11380A>G		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.2564-11380A>G		intron_variant	Intron 15 of 20	1	NM_001367233.3	ENSP00000343939.2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 42386 AN: 112068 Hom.: 9376 Cov.: 25

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.0915

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.312

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

GnomAD4 genome AF: 0.379 AC: 42451 AN: 112121 Hom.: 9385 Cov.: 25 AF XY: 0.365 AC XY: 12552 AN XY: 34351

African (AFR) AF: 0.861 AC: 26635 AN: 30934

American (AMR) AF: 0.258 AC: 2755 AN: 10689

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 234 AN: 2629

East Asian (EAS) AF: 0.00112 AC: 4 AN: 3558

South Asian (SAS) AF: 0.0921 AC: 254 AN: 2757

European-Finnish (FIN) AF: 0.240 AC: 1462 AN: 6090

Middle Eastern (MID) AF: 0.220 AC: 48 AN: 218

European-Non Finnish (NFE) AF: 0.198 AC: 10489 AN: 53023

Other (OTH) AF: 0.309 AC: 475 AN: 1535

Alfa AF: 0.211 Hom.: 5668

Bravo AF: 0.399

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.3
DANN	Benign	0.49
PhyloP100		-1.4
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: rs1068536; hg19: chrX-65463497;