1-46689619-C-G

Variant names:

• chr1-46689619-C-G
• rs200564580
• NM_014774.3:c.763G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_014774.3(EFCAB14):​c.763G>C​(p.Asp255His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,884 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 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: EFCAB14 NM_014774.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2912805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB14	NM_014774.3	c.763G>C	p.Asp255His	missense_variant	Exon 6 of 11	ENST00000371933.8	NP_055589.1
EFCAB14-AS1	NR_038827.1	n.360-2255C>G		intron_variant	Intron 3 of 3
EFCAB14-AS1	NR_038828.1	n.276-2255C>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFCAB14	ENST00000371933.8	c.763G>C	p.Asp255His	missense_variant	Exon 6 of 11	1	NM_014774.3	ENSP00000361001.3

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251266 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000109 AC: 160 AN: 1461558 Hom.: 0 Cov.: 30 AF XY: 0.000110 AC XY: 80 AN XY: 727084

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33448

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44706

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26128

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86240

Gnomad4 FIN exome AF: 0.0000187 AC: 1 AN: 53420

Gnomad4 NFE exome AF: 0.000141 AC: 157 AN: 1111780

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74476

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

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: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000206 AC: 0.000205779 AN: 0.000205779

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.763G>C (p.D255H) alteration is located in exon 6 (coding exon 6) of the EFCAB14 gene. This alteration results from a G to C substitution at nucleotide position 763, causing the aspartic acid (D) at amino acid position 255 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	0.14
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.29	T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.093	T
Polyphen		1.0	D
Vest4		0.17
MVP		0.86
MPC		0.63
ClinPred		0.32	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.14
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200564580; hg19: chr1-47155291;