chr1-46691829-T-C

Position:

• chr1-46691829-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014774.3(EFCAB14):​c.688A>G​(p.Met230Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EFCAB14 NM_014774.3 missense, splice_region
• Scores: Splicing: ADA: 0.0001966
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.10

Genes affected

EFCAB14 (HGNC:29051): (EF-hand calcium binding domain 14) Predicted to enable calcium ion binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

EFCAB14-AS1 (HGNC:44108): (EFCAB14 antisense RNA 1)

ACMG classification

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=0.042437702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFCAB14	NM_014774.3	c.688A>G	p.Met230Val	missense_variant, splice_region_variant	5/11	ENST00000371933.8	NP_055589.1
EFCAB14-AS1	NR_038827.1	n.360-45T>C		intron_variant, non_coding_transcript_variant
EFCAB14-AS1	NR_038828.1	n.276-45T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFCAB14	ENST00000371933.8	c.688A>G	p.Met230Val	missense_variant, splice_region_variant	5/11	1	NM_014774.3	ENSP00000361001	P2
EFCAB14-AS1	ENST00000442839.5	n.276-45T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459768 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726194

Gnomad4 AFR exome AF: 0.0000300

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: 0.00

GnomAD4 genome Cov.: 33

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

Oct 25, 2023

The c.688A>G (p.M230V) alteration is located in exon 5 (coding exon 5) of the EFCAB14 gene. This alteration results from a A to G substitution at nucleotide position 688, causing the methionine (M) at amino acid position 230 to be replaced by a valine (V). 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	0.068
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	2.8
DANN	Benign	0.82
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.19
Sift	Benign	0.48	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.17		Loss of disorder (P = 0.1052);
MVP		0.58
MPC		0.13
ClinPred		0.068	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-47157501;