chr2-232662830-G-A

Position:

• chr2-232662830-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_025202.4(EFHD1):​c.331G>A​(p.Asp111Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,431,872 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: EFHD1 NM_025202.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHD1	NM_025202.4	c.331G>A	p.Asp111Asn	missense_variant	2/4	ENST00000264059.8	NP_079478.1
EFHD1	NM_001243252.2	c.43G>A	p.Asp15Asn	missense_variant	2/4		NP_001230181.1
EFHD1	NM_001308395.2	c.-6G>A		5_prime_UTR_variant	3/5		NP_001295324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHD1	ENST00000264059.8	c.331G>A	p.Asp111Asn	missense_variant	2/4	1	NM_025202.4	ENSP00000264059	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1431872 Hom.: 0 Cov.: 30 AF XY: 0.00000421 AC XY: 3 AN XY: 712046

Gnomad4 AFR exome AF: 0.0000320

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: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.331G>A (p.D111N) alteration is located in exon 2 (coding exon 2) of the EFHD1 gene. This alteration results from a G to A substitution at nucleotide position 331, causing the aspartic acid (D) at amino acid position 111 to be replaced by an asparagine (N). 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	0.31
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	.;T;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Benign	0.34	.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.3	D;D;.
REVEL	Uncertain	0.56
Sift	Benign	0.084	T;T;.
Sift4G	Benign	0.072	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.94
MutPred		0.60		.;Gain of ubiquitination at K116 (P = 0.1204);.;
MVP		0.53
MPC		0.50
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.46
gMVP		0.77

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: rs11550700; hg19: chr2-233527540; COSMIC: COSV51132345;