X-66162843-T-C

Variant names:

• chrX-66162843-T-C
• rs5919015
• ENST00000519389.6:c.-47T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000519389.6(HEPH):​c.-47T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.80 (25410 hom., 25897 hem., cov: 22)
  • Exomes 𝑓: 0.71 (178935 hom. 244428 hem.)
  • Failed GnomAD Quality Control
• Consequence: HEPH ENST00000519389.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.179
• Publications: 28 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7057484E-6).
• BP6: Variant X-66162843-T-C is Benign according to our data. Variant chrX-66162843-T-C is described in CliVar as Benign. Clinvar id is 3256843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEPH	XM_011531073.4	c.116T>C	p.Val39Ala	missense_variant	Exon 1 of 21		XP_011529375.1
HEPH	XM_047442694.1	c.79T>C	p.Cys27Arg	missense_variant	Exon 1 of 21		XP_047298650.1
HEPH	XM_011531074.3	c.116T>C	p.Val39Ala	missense_variant	Exon 1 of 20		XP_011529376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEPH	ENST00000519389.6	c.-47T>C		5_prime_UTR_variant	Exon 1 of 21	1		ENSP00000430620.2

Frequencies

GnomAD3 genomes AF: 0.799 AC: 87891 AN: 109943 Hom.: 25409 Cov.: 22

Gnomad AFR AF: 0.957

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.867

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.924

Gnomad FIN AF: 0.731

Gnomad MID AF: 0.900

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.841

GnomAD2 exomes AF: 0.812 AC: 83724 AN: 103057 AF XY: 0.812

Gnomad AFR exome AF: 0.965

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.865

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.717

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.813

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.710 AC: 740343 AN: 1042502 Hom.: 178935 Cov.: 34 AF XY: 0.717 AC XY: 244428 AN XY: 341134

African (AFR) AF: 0.964 AC: 23996 AN: 24891

American (AMR) AF: 0.910 AC: 25375 AN: 27871

Ashkenazi Jewish (ASJ) AF: 0.865 AC: 16115 AN: 18630

East Asian (EAS) AF: 1.00 AC: 27113 AN: 27126

South Asian (SAS) AF: 0.909 AC: 45307 AN: 49845

European-Finnish (FIN) AF: 0.723 AC: 19335 AN: 26732

Middle Eastern (MID) AF: 0.931 AC: 3803 AN: 4083

European-Non Finnish (NFE) AF: 0.666 AC: 545562 AN: 819024

Other (OTH) AF: 0.762 AC: 33737 AN: 44300

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.800 AC: 87951 AN: 109998 Hom.: 25410 Cov.: 22 AF XY: 0.804 AC XY: 25897 AN XY: 32206

African (AFR) AF: 0.957 AC: 28969 AN: 30267

American (AMR) AF: 0.875 AC: 8968 AN: 10248

Ashkenazi Jewish (ASJ) AF: 0.867 AC: 2285 AN: 2636

East Asian (EAS) AF: 0.999 AC: 3481 AN: 3485

South Asian (SAS) AF: 0.924 AC: 2339 AN: 2532

European-Finnish (FIN) AF: 0.731 AC: 4202 AN: 5751

Middle Eastern (MID) AF: 0.914 AC: 191 AN: 209

European-Non Finnish (NFE) AF: 0.680 AC: 35824 AN: 52702

Other (OTH) AF: 0.843 AC: 1264 AN: 1500

Alfa AF: 0.732 Hom.: 121838

Bravo AF: 0.822

TwinsUK AF: 0.666 AC: 2470

ALSPAC AF: 0.656 AC: 1894

ESP6500AA AF: 0.968 AC: 1170

ESP6500EA AF: 0.689 AC: 1647

ExAC AF: 0.826 AC: 15731

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 90% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 84. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.7
DANN	Benign	0.54
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.18
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Vest4		0.011
MPC		0.096
ClinPred		0.0035	T
GERP RS		-4.4
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.25
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs5919015; hg19: chrX-65382685; COSMIC: COSV60357976; COSMIC: COSV60357976;