rs149998588

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2

The NM_018100.4(EFHC1):c.1612C>T(p.Arg538Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

EFHC1
NM_018100.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 1.28

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 Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 6-52479759-C-T is Pathogenic according to our data. Variant chr6-52479759-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205414.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.

BS2

High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EFHC1	NM_018100.4 linkuse as main transcript	c.1612C>T	p.Arg538Ter	stop_gained	9/11	ENST00000371068.11
EFHC1	NM_001172420.2 linkuse as main transcript	c.1555C>T	p.Arg519Ter	stop_gained	10/12
EFHC1	NR_033327.2 linkuse as main transcript	n.2938C>T		non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11 linkuse as main transcript	c.1612C>T	p.Arg538Ter	stop_gained	9/11	1	NM_018100.4	P1	Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251336

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000885

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Juvenile myoclonic epilepsy

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory paternally inherited in a 15-year-old female with intellectual disability, epilepsy (first afebrile tonic/clonic seizures at 3y, subsided until 11 years), hypotonia. Father did not have epilepsy. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 06, 2018	The EFHC1 c.1612C>T (p.Arg538Ter) variant is a stop gained variant predicted to result in premature termination of the protein. The p.Arg538Ter variant has not been reported in the literature in association with juvenile myoclonic epilepsy. Control data are unavailable for this variant, which is found at a frequency of 0.0004961 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for juvenile myoclonic epilepsy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2013

p.Arg538Stop (CGA>TGA): c.1612 C>T in exon 9 of the EFHC1 gene (NM_018100.3). The Arg538Stop nonsense mutation in the EFHC1 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been reported previously to our knowledge, it is considered a disease-causing mutation. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.28

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.28

Eigen_PC

Benign

-0.00076

FATHMM_MKL

Benign

0.17

MutationTaster

Benign

1.0

A;A;A

Vest4

0.74, 0.74

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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