1-63568421-C-A

Variant summary

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

The NM_032437.4(EFCAB7):c.1609C>A(p.Leu537Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,434,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: EFCAB7 NM_032437.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

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]

ITGB3BP (HGNC:6157): (integrin subunit beta 3 binding protein) This gene encodes a transcriptional coregulator that binds to and enhances the activity of members of the nuclear receptor families, thyroid hormone receptors and retinoid X receptors. This protein also acts as a corepressor of NF-kappaB-dependent signaling. This protein induces apoptosis in breast cancer cells through a caspase 2-mediated signaling pathway. This protein is also a component of the centromere-specific histone H3 variant nucleosome associated complex (CENP-NAC) and may be involved in mitotic progression by recruiting the histone H3 variant CENP-A to the centromere. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

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=0.02856195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFCAB7	NM_032437.4	c.1609C>A	p.Leu537Ile	missense_variant	12/14	ENST00000371088.5
EFCAB7	XM_006710976.4	c.1648C>A	p.Leu550Ile	missense_variant	12/14
EFCAB7	XM_006710977.2	c.1609C>A	p.Leu537Ile	missense_variant	12/14
EFCAB7	XM_011542301.3	c.1648C>A	p.Leu550Ile	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFCAB7	ENST00000371088.5	c.1609C>A	p.Leu537Ile	missense_variant	12/14	1	NM_032437.4	P1
EFCAB7	ENST00000460678.6	n.891C>A		non_coding_transcript_exon_variant	6/7	5
EFCAB7	ENST00000461039.1	n.836C>A		non_coding_transcript_exon_variant	4/5	2
ITGB3BP	ENST00000478138.1	n.197+25104G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000838 AC: 19 AN: 226610 Hom.: 0 AF XY: 0.0000487 AC XY: 6 AN XY: 123088

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000544

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.000187

GnomAD4 exome AF: 0.0000174 AC: 25 AN: 1434134 Hom.: 0 Cov.: 30 AF XY: 0.0000112 AC XY: 8 AN XY: 712942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000512

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: 0.00000273

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000509 Hom.: 0

ExAC AF: 0.0000988 AC: 12

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

Feb 10, 2022

The c.1609C>A (p.L537I) alteration is located in exon 12 (coding exon 11) of the EFCAB7 gene. This alteration results from a C to A substitution at nucleotide position 1609, causing the leucine (L) at amino acid position 537 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	0.068
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	17
Dann	Benign	0.94
DEOGEN2	Benign	0.00059	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.060
Sift	Benign	0.58	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.12		Loss of catalytic residue at L537 (P = 0.0836);
MVP		0.42
MPC		0.17
ClinPred		0.033	T
GERP RS		2.6
Varity_R		0.083
gMVP		0.089

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: rs751196573; hg19: chr1-64034092;