rs3804506

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018100.4(EFHC1):c.475C>G(p.Arg159Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,906 control chromosomes in the GnomAD database, including 38 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0099 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 20 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.03

Variant links:

Genes affected

EFHC1 (HGNC:16406): (EF-hand domain containing 1) This gene encodes an EF-hand-containing calcium binding protein. The encoded protein likely plays a role in calcium homeostasis. Mutations in this gene have been associated with susceptibility to juvenile myoclonic epilepsy and juvenile absence epilepsy. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

EFHC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002821058).

BP6

Variant 6-52438493-C-G is Benign according to our data. Variant chr6-52438493-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 196484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52438493-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00987 (1502/152156) while in subpopulation AFR AF= 0.0347 (1442/41510). AF 95% confidence interval is 0.0332. There are 18 homozygotes in gnomad4. There are 660 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1502 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EFHC1	NM_018100.4 linkuse as main transcript	c.475C>G	p.Arg159Gly	missense_variant	3/11	ENST00000371068.11
EFHC1	NM_001172420.2 linkuse as main transcript	c.418C>G	p.Arg140Gly	missense_variant	4/12
EFHC1	NR_033327.2 linkuse as main transcript	n.544C>G		non_coding_transcript_exon_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11 linkuse as main transcript	c.475C>G	p.Arg159Gly	missense_variant	3/11	1	NM_018100.4	P1	Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.00986

AC:

1499

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00528

GnomAD3 exomes

AF:

0.00274

AC:

688

AN:

251084

Hom.:

AF XY:

0.00189

AC XY:

257

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.0378

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.00102

AC:

1489

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000894

AC XY:

650

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0363

Gnomad4 AMR exome

AF:

0.00222

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00220

GnomAD4 genome

AF:

0.00987

AC:

1502

AN:

152156

Hom.:

Cov.:

AF XY:

0.00887

AC XY:

660

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0347

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.0000560

Hom.:

1761

ExAC

AF:

0.00360

AC:

437

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Absence seizure;C1850778:Myoclonic epilepsy, juvenile, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Dec 09, 2016

- -

EFHC1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 01, 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

0.085

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.028

T;.;.;T;T;T;T;T;T;.;.;.;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.95

D;D;.;D;D;D;D;D;D;D;.;D;D

MetaRNN

Benign

0.0028

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;.;.;L;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.18

PROVEAN

Benign

-2.2

.;.;.;N;.;.;.;.;.;.;.;.;N

REVEL

Benign

0.096

Sift

Benign

0.33

.;.;.;T;.;.;.;.;.;.;.;.;T

Sift4G

Benign

0.33

.;.;.;T;.;.;.;.;.;.;.;.;T

Polyphen

0.0010

.;.;.;B;.;.;.;.;.;.;.;.;.

Vest4

0.21, 0.20

MVP

0.67

MPC

0.11

ClinPred

0.0042

GERP RS

2.7

Varity_R

0.085

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over