17-62391847-C-G

Position:

• chr17-62391847-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_173503.4(EFCAB3):​c.177C>G​(p.Phe59Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EFCAB3 NM_173503.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

Genes affected

EFCAB3 (HGNC:26379): (EF-hand calcium binding domain 3) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

EFCAB3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFCAB3	NM_173503.4	c.177C>G	p.Phe59Leu	missense_variant	4/10	ENST00000305286.8	NP_775774.1
EFCAB3	NM_001144933.2	c.333C>G	p.Phe111Leu	missense_variant	6/12		NP_001138405.1
EFCAB3	XM_011524381.3	c.243C>G	p.Phe81Leu	missense_variant	4/10		XP_011522683.2
EFCAB3	XM_011524380.2	c.177C>G	p.Phe59Leu	missense_variant	4/10		XP_011522682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFCAB3	ENST00000305286.8	c.177C>G	p.Phe59Leu	missense_variant	4/10	1	NM_173503.4	ENSP00000302649.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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 20, 2024

The c.333C>G (p.F111L) alteration is located in exon 6 (coding exon 6) of the EFCAB3 gene. This alteration results from a C to G substitution at nucleotide position 333, causing the phenylalanine (F) at amino acid position 111 to be replaced by a leucine (L). 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.5	.;M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.85
MutPred		0.88		.;Loss of stability (P = 0.0621);Loss of stability (P = 0.0621);Loss of stability (P = 0.0621);
MVP		0.84
MPC		0.70
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.77
gMVP		0.49

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: rs2070305326; hg19: chr17-60469208;