1-63532716-T-G

Position:

• chr1-63532716-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032437.4(EFCAB7):​c.446T>G​(p.Leu149Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: EFCAB7 NM_032437.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22

Genes affected

EFCAB7 (HGNC:29379): (EF-hand calcium binding domain 7) Predicted to enable calcium ion binding activity. Predicted to be involved in positive regulation of protein import into nucleus; positive regulation of protein localization to ciliary membrane; and positive regulation of transcription by RNA polymerase II. Predicted to be located in ciliary membrane. Predicted to be extrinsic component of membrane. Predicted to be part of plasma membrane protein complex. [provided by Alliance of Genome Resources, Apr 2022]

EFCAB7 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFCAB7	NM_032437.4	c.446T>G	p.Leu149Trp	missense_variant	4/14	ENST00000371088.5	NP_115813.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFCAB7	ENST00000371088.5	c.446T>G	p.Leu149Trp	missense_variant	4/14	1	NM_032437.4	ENSP00000360129.4
ITGB3BP	ENST00000478138.1	n.198-3530A>C		intron_variant		3
EFCAB7	ENST00000480886.1	n.*20T>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jun 29, 2023

The c.446T>G (p.L149W) alteration is located in exon 4 (coding exon 3) of the EFCAB7 gene. This alteration results from a T to G substitution at nucleotide position 446, causing the leucine (L) at amino acid position 149 to be replaced by a tryptophan (W). 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	0.26
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.59		Loss of stability (P = 0.0584);
MVP		0.63
MPC		0.85
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-63998387;