1-63533523-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032437.4(EFCAB7):c.556A>G(p.Ser186Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,414 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0099 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: EFCAB7 NM_032437.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.66

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030931234).
• BP6: Variant 1-63533523-A-G is Benign according to our data. Variant chr1-63533523-A-G is described in ClinVar as [Benign]. Clinvar id is 720628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00988 (1505/152264) while in subpopulation AFR AF= 0.0331 (1377/41550). AF 95% confidence interval is 0.0317. There are 23 homozygotes in gnomad4. There are 676 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFCAB7	NM_032437.4	c.556A>G	p.Ser186Gly	missense_variant	5/14	ENST00000371088.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFCAB7	ENST00000371088.5	c.556A>G	p.Ser186Gly	missense_variant	5/14	1	NM_032437.4	P1
ITGB3BP	ENST00000478138.1	n.198-4337T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 1504 AN: 152146 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00254 AC: 638 AN: 250770 Hom.: 10 AF XY: 0.00187 AC XY: 254 AN XY: 135574

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00109 AC: 1594 AN: 1461150 Hom.: 25 Cov.: 31 AF XY: 0.000930 AC XY: 676 AN XY: 726912

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000303

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00988 AC: 1505 AN: 152264 Hom.: 23 Cov.: 32 AF XY: 0.00908 AC XY: 676 AN XY: 74458

Gnomad4 AFR AF: 0.0331

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00627 Hom.: 4

Bravo AF: 0.0111

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00298 AC: 362

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000475

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 25, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	16
Dann	Benign	0.77
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.072
Sift	Benign	0.064	T
Sift4G	Benign	0.16	T
Polyphen		0.010	B
Vest4		0.044
MVP		0.35
MPC		0.15
ClinPred		0.0077	T
GERP RS		3.6
Varity_R		0.074
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9436246; hg19: chr1-63999194;