X-66196245-G-A

Variant names:

• chrX-66196245-G-A
• rs1011526
• NM_001367233.3:c.1501+1016G>A

Variant summary

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

The NM_001367233.3(HEPH):​c.1501+1016G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 110,338 control chromosomes in the GnomAD database, including 9,518 homozygotes. There are 12,116 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 0.39 (9518 hom., 12116 hem., cov: 22)
• Consequence: HEPH NM_001367233.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.142
• Publications: 6 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 = 0.849 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.1501+1016G>A		intron	N/A	NP_001354162.2
	HEPH	NM_001367232.3		c.1501+1016G>A		intron	N/A	NP_001354161.2
	HEPH	NM_001367234.3		c.1501+1016G>A		intron	N/A	NP_001354163.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPH	ENST00000343002.7	TSL:1 MANE Select	c.1501+1016G>A		intron	N/A	ENSP00000343939.2
	HEPH	ENST00000519389.6	TSL:1	c.1501+1016G>A		intron	N/A	ENSP00000430620.2
	HEPH	ENST00000441993.7	TSL:1	c.1501+1016G>A		intron	N/A	ENSP00000411687.3

Frequencies

GnomAD3 genomes AF: 0.390 AC: 42967 AN: 110286 Hom.: 9508 Cov.: 22

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.00140

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.324

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

GnomAD4 genome AF: 0.390 AC: 43032 AN: 110338 Hom.: 9518 Cov.: 22 AF XY: 0.372 AC XY: 12116 AN XY: 32602

African (AFR) AF: 0.857 AC: 25974 AN: 30292

American (AMR) AF: 0.260 AC: 2703 AN: 10386

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 545 AN: 2624

East Asian (EAS) AF: 0.00141 AC: 5 AN: 3551

South Asian (SAS) AF: 0.101 AC: 268 AN: 2643

European-Finnish (FIN) AF: 0.252 AC: 1444 AN: 5720

Middle Eastern (MID) AF: 0.233 AC: 50 AN: 215

European-Non Finnish (NFE) AF: 0.217 AC: 11458 AN: 52729

Other (OTH) AF: 0.323 AC: 483 AN: 1497

Alfa AF: 0.262 Hom.: 20917

Bravo AF: 0.411

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.0
DANN	Benign	0.84
PhyloP100		0.14
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: rs1011526; hg19: chrX-65416087;