Variant 2-232633823-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025202.4(EFHD1):c.119C>A(p.Pro40His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,475,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

EFHD1
NM_025202.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.237

Variant links:

Genes affected

EFHD1 (HGNC:29556): (EF-hand domain family member D1) This gene encodes a member of the EF-hand super family of calcium binding proteins, which are involved in a variety of cellular processes including mitosis, synaptic transmission, and cytoskeletal rearrangement. The protein encoded by this gene is composed of an N-terminal disordered region, proline-rich elements, two EF-hands, and a C-terminal coiled-coil domain. This protein has been shown to associate with the mitochondrial inner membrane, and in HeLa cells, acts as a novel mitochondrial calcium ion sensor for mitochondrial flash activation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

EFHD1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018303096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EFHD1	NM_025202.4 linkuse as main transcript	c.119C>A	p.Pro40His	missense_variant	1/4	ENST00000264059.8	NP_079478.1
EFHD1	NM_001308395.2 linkuse as main transcript	c.-297C>A		5_prime_UTR_variant	1/5		NP_001295324.1
EFHD1	NM_001243252.2 linkuse as main transcript	c.14+27650C>A		intron_variant			NP_001230181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHD1	ENST00000264059.8 linkuse as main transcript	c.119C>A	p.Pro40His	missense_variant	1/4	1	NM_025202.4	ENSP00000264059	P1	Q9BUP0-1
EFHD1	ENST00000409613.5 linkuse as main transcript	c.14+27650C>A		intron_variant		1		ENSP00000386556		Q9BUP0-2
EFHD1	ENST00000442845.1 linkuse as main transcript	c.110C>A	p.Pro37His	missense_variant, NMD_transcript_variant	1/5	3		ENSP00000395119

Frequencies

GnomAD3 genomes

AF:

0.000580

AC:

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00206

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000394

AC:

AN:

76192

Hom.:

AF XY:

0.0000458

AC XY:

AN XY:

43660

show subpopulations

Gnomad AFR exome

AF:

0.00214

Gnomad AMR exome

AF:

0.0000673

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000574

AC:

AN:

1323682

Hom.:

Cov.:

AF XY:

0.0000491

AC XY:

AN XY:

652152

show subpopulations

Gnomad4 AFR exome

AF:

0.00250

Gnomad4 AMR exome

AF:

0.0000749

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.48e-7

Gnomad4 OTH exome

AF:

0.000127

GnomAD4 genome

AF:

0.000580

AC:

AN:

151776

Hom.:

Cov.:

AF XY:

0.000553

AC XY:

AN XY:

74136

show subpopulations

Gnomad4 AFR

AF:

0.00206

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000646

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.119C>A (p.P40H) alteration is located in exon 1 (coding exon 1) of the EFHD1 gene. This alteration results from a C to A substitution at nucleotide position 119, causing the proline (P) at amino acid position 40 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.017

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.28

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.84

REVEL

Benign

0.079

Sift

Benign

0.083

Sift4G

Uncertain

0.036

Polyphen

0.0010

Vest4

0.16

MVP

0.40

MPC

1.8

ClinPred

0.028

GERP RS

1.4

Varity_R

0.065

gMVP

0.46

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

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