X-66215415-T-G

Variant names:

• chrX-66215415-T-G
• rs1264216
• NM_001367233.3:c.2563+7169T>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.2563+7169T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 110,099 control chromosomes in the GnomAD database, including 4,247 homozygotes. There are 8,746 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 0.29 (4247 hom., 8746 hem., cov: 22)
• Consequence: HEPH NM_001367233.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.760
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPH	NM_001367233.3	MANE Select	c.2563+7169T>G		intron	N/A	NP_001354162.2	Q1HE23
	HEPH	NM_001367232.3		c.2563+7169T>G		intron	N/A	NP_001354161.2	Q1HE23
	HEPH	NM_001367234.3		c.2563+7169T>G		intron	N/A	NP_001354163.2	Q1HE23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPH	ENST00000343002.7	TSL:1 MANE Select	c.2563+7169T>G		intron	N/A	ENSP00000343939.2	Q9BQS7-1
	HEPH	ENST00000519389.6	TSL:1	c.2563+7169T>G		intron	N/A	ENSP00000430620.2	Q9BQS7-1
	HEPH	ENST00000441993.7	TSL:1	c.2563+7169T>G		intron	N/A	ENSP00000411687.3	Q9BQS7-2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 31761 AN: 110049 Hom.: 4247 Cov.: 22

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.00168

Gnomad SAS AF: 0.0983

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.208

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.242

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

GnomAD4 genome AF: 0.289 AC: 31796 AN: 110099 Hom.: 4247 Cov.: 22 AF XY: 0.270 AC XY: 8746 AN XY: 32415

African (AFR) AF: 0.511 AC: 15384 AN: 30079

American (AMR) AF: 0.220 AC: 2274 AN: 10325

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 528 AN: 2631

East Asian (EAS) AF: 0.00168 AC: 6 AN: 3570

South Asian (SAS) AF: 0.0998 AC: 259 AN: 2595

European-Finnish (FIN) AF: 0.244 AC: 1392 AN: 5713

Middle Eastern (MID) AF: 0.205 AC: 44 AN: 215

European-Non Finnish (NFE) AF: 0.217 AC: 11451 AN: 52792

Other (OTH) AF: 0.240 AC: 360 AN: 1500

Alfa AF: 0.242 Hom.: 23018

Bravo AF: 0.300

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.81
PhyloP100		0.76
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: rs1264216; hg19: chrX-65435257;