Variant 2-232633849-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000264059.8(EFHD1):c.145G>C(p.Ala49Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000742 in 1,348,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

EFHD1
ENST00000264059.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.96

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35234672).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EFHD1	NM_025202.4 linkuse as main transcript	c.145G>C	p.Ala49Pro	missense_variant	1/4	ENST00000264059.8	NP_079478.1
EFHD1	NM_001308395.2 linkuse as main transcript	c.-271G>C		5_prime_UTR_variant	1/5		NP_001295324.1
EFHD1	NM_001243252.2 linkuse as main transcript	c.14+27676G>C		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.145G>C	p.Ala49Pro	missense_variant	1/4	1	NM_025202.4	ENSP00000264059	P1	Q9BUP0-1
EFHD1	ENST00000409613.5 linkuse as main transcript	c.14+27676G>C		intron_variant		1		ENSP00000386556		Q9BUP0-2
EFHD1	ENST00000442845.1 linkuse as main transcript	c.136G>C	p.Ala46Pro	missense_variant, NMD_transcript_variant	1/5	3		ENSP00000395119

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000998

AC:

AN:

100182

Hom.:

AF XY:

0.0000176

AC XY:

AN XY:

56660

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000187

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:

7.42e-7

AC:

AN:

1348282

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

665120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000108

AC:

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

Jul 27, 2022

The c.145G>C (p.A49P) alteration is located in exon 1 (coding exon 1) of the EFHD1 gene. This alteration results from a G to C substitution at nucleotide position 145, causing the alanine (A) at amino acid position 49 to be replaced by a proline (P). 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

0.087

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0098

Eigen

Benign

-0.061

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.36

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.99

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.1

REVEL

Benign

0.13

Sift

Benign

0.11

Sift4G

Benign

0.20

Polyphen

0.97

Vest4

0.22

MutPred

0.19

Gain of glycosylation at A49 (P = 0.0466);

MVP

0.53

MPC

2.0

ClinPred

0.29

GERP RS

2.9

Varity_R

0.30

gMVP

0.48

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