dbSNP rs151059690: EFCAB7:p.Lys162Gln (chr1-63532754-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032437.4(EFCAB7):c.484A>C(p.Lys162Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000208 in 1,444,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K162E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EFCAB7
NM_032437.4 missense, splice_region

Scores

Splicing: ADA: 0.4226

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.62

Variant links:

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 links:

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]

ITGB3BP links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB7	NM_032437.4 link	c.484A>C	p.Lys162Gln	missense_variant, splice_region_variant	Exon 4 of 14	ENST00000371088.5	NP_115813.2	A8K855-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EFCAB7	ENST00000371088.5 link	c.484A>C	p.Lys162Gln	missense_variant, splice_region_variant	Exon 4 of 14	1	NM_032437.4	ENSP00000360129.4	A8K855-1
ITGB3BP	ENST00000478138.1 link	n.198-3568T>G		intron_variant	Intron 1 of 4	3
EFCAB7	ENST00000480886.1 link	n.*58A>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1444994

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.0010

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.82

REVEL

Uncertain

0.29

Sift

Uncertain

0.028

Sift4G

Uncertain

0.035

Polyphen

0.99

Vest4

0.43

MutPred

0.60

Loss of methylation at K162 (P = 0.0038);

MVP

0.79

MPC

0.30

ClinPred

0.89

GERP RS

4.5

Varity_R

0.30

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.42

dbscSNV1_RF

Benign

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over