1-46691898-G-T

Variant names:

• chr1-46691898-G-T
• rs141692192
• NM_014774.3:c.619C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014774.3(EFCAB14):​c.619C>A​(p.Leu207Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000451 in 1,613,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: EFCAB14 NM_014774.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.93

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20432901).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB14	NM_014774.3	c.619C>A	p.Leu207Ile	missense_variant	Exon 5 of 11	ENST00000371933.8	NP_055589.1
EFCAB14-AS1	NR_038827.1	n.384G>T		non_coding_transcript_exon_variant	Exon 4 of 4
EFCAB14-AS1	NR_038828.1	n.300G>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFCAB14	ENST00000371933.8	c.619C>A	p.Leu207Ile	missense_variant	Exon 5 of 11	1	NM_014774.3	ENSP00000361001.3

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000239 AC: 60 AN: 250776 AF XY: 0.000236

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000494

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000472 AC: 690 AN: 1461236 Hom.: 0 Cov.: 30 AF XY: 0.000424 AC XY: 308 AN XY: 726908

Gnomad4 AFR exome AF: 0.0000598 AC: 2 AN: 33434

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44632

Gnomad4 ASJ exome AF: 0.0000766 AC: 2 AN: 26116

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39680

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86220

Gnomad4 FIN exome AF: 0.0000562 AC: 3 AN: 53368

Gnomad4 NFE exome AF: 0.000593 AC: 659 AN: 1111678

Gnomad4 Remaining exome AF: 0.000398 AC: 24 AN: 60346

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74356

Gnomad4 AFR AF: 0.0000483 AC: 0.0000482556 AN: 0.0000482556

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000942 AC: 0.0000941797 AN: 0.0000941797

Gnomad4 NFE AF: 0.000500 AC: 0.00049975 AN: 0.00049975

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000403 Hom.: 0

Bravo AF: 0.000295

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.619C>A (p.L207I) alteration is located in exon 5 (coding exon 5) of the EFCAB14 gene. This alteration results from a C to A substitution at nucleotide position 619, causing the leucine (L) at amino acid position 207 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.16
Sift	Benign	0.27	T
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.32
MVP		0.75
MPC		0.60
ClinPred		0.10	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.087
gMVP		0.11
Mutation Taster		=88/12	polymorphism

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: rs141692192; hg19: chr1-47157570;