11-94064453-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001098672.2(HEPHL1):c.751A>G(p.Asn251Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,612,948 control chromosomes in the GnomAD database, including 787,298 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.93 (66380 hom., cov: 32)
  • Exomes 𝑓: 0.99 (720918 hom.)
• Consequence: HEPHL1 NM_001098672.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.848

Genes affected

HEPHL1 (HGNC:30477): (hephaestin like 1) Enables ferroxidase activity. Involved in cellular iron ion homeostasis. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4735017E-6).
• BP6: Variant 11-94064453-A-G is Benign according to our data. Variant chr11-94064453-A-G is described in ClinVar as [Benign]. Clinvar id is 1285336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEPHL1	NM_001098672.2	c.751A>G	p.Asn251Asp	missense_variant	4/20	ENST00000315765.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEPHL1	ENST00000315765.10	c.751A>G	p.Asn251Asp	missense_variant	4/20	5	NM_001098672.2	P1

Frequencies

GnomAD3 genomes AF: 0.928 AC: 141071 AN: 152096 Hom.: 66340 Cov.: 32

Gnomad AFR AF: 0.748

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.946

GnomAD3 exomes AF: 0.981 AC: 244138 AN: 248760 Hom.: 120298 AF XY: 0.986 AC XY: 133103 AN XY: 134968

Gnomad AFR exome AF: 0.738

Gnomad AMR exome AF: 0.989

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.990

GnomAD4 exome AF: 0.993 AC: 1450098 AN: 1460734 Hom.: 720918 Cov.: 36 AF XY: 0.994 AC XY: 722114 AN XY: 726662

Gnomad4 AFR exome AF: 0.743

Gnomad4 AMR exome AF: 0.987

Gnomad4 ASJ exome AF: 0.998

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.984

GnomAD4 genome AF: 0.927 AC: 141171 AN: 152214 Hom.: 66380 Cov.: 32 AF XY: 0.931 AC XY: 69251 AN XY: 74414

Gnomad4 AFR AF: 0.748

Gnomad4 AMR AF: 0.973

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.946

Alfa AF: 0.985 Hom.: 155789

Bravo AF: 0.917

TwinsUK AF: 0.999 AC: 3706

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.747 AC: 2780

ESP6500EA AF: 0.999 AC: 8189

ExAC AF: 0.977 AC: 118039

Asia WGS AF: 0.984 AC: 3421 AN: 3476

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pili torti-developmental delay-neurological abnormalities syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

HEPHL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.41
Dann	Benign	0.18
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.032	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.67	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.27
Sift	Benign	0.94	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0060
MPC		0.042
ClinPred		0.000012	T
GERP RS		2.1
Varity_R		0.024
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs1945783; hg19: chr11-93797619;