1-63561783-C-G

Position:

• chr1-63561783-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032437.4(EFCAB7):​c.1423C>G​(p.Arg475Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000798 in 1,608,532 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: EFCAB7 NM_032437.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009561032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFCAB7	NM_032437.4	c.1423C>G	p.Arg475Gly	missense_variant	11/14	ENST00000371088.5	NP_115813.2
EFCAB7	XM_006710976.4	c.1462C>G	p.Arg488Gly	missense_variant	11/14		XP_006711039.1
EFCAB7	XM_006710977.2	c.1423C>G	p.Arg475Gly	missense_variant	11/14		XP_006711040.1
EFCAB7	XM_011542301.3	c.1462C>G	p.Arg488Gly	missense_variant	11/14		XP_011540603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFCAB7	ENST00000371088.5	c.1423C>G	p.Arg475Gly	missense_variant	11/14	1	NM_032437.4	ENSP00000360129.4
EFCAB7	ENST00000460678.6	n.705C>G		non_coding_transcript_exon_variant	5/7	5
EFCAB7	ENST00000461039.1	n.650C>G		non_coding_transcript_exon_variant	3/5	2
ITGB3BP	ENST00000478138.1	n.197+31742G>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152090 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000501 AC: 125 AN: 249526 Hom.: 0 AF XY: 0.000445 AC XY: 60 AN XY: 134944

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000929

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000814 AC: 1186 AN: 1456324 Hom.: 1 Cov.: 29 AF XY: 0.000755 AC XY: 547 AN XY: 724568

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.000615

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.0000940

Gnomad4 NFE exome AF: 0.000998

Gnomad4 OTH exome AF: 0.000649

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152208 Hom.: 1 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74418

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000552 Hom.: 0

Bravo AF: 0.000654

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000610 AC: 74

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

May 23, 2024

The c.1423C>G (p.R475G) alteration is located in exon 11 (coding exon 10) of the EFCAB7 gene. This alteration results from a C to G substitution at nucleotide position 1423, causing the arginine (R) at amino acid position 475 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.13
Sift	Benign	0.032	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.72	P
Vest4		0.28
MVP		0.41
MPC		0.21
ClinPred		0.040	T
GERP RS		2.8
Varity_R		0.15
gMVP		0.22

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: rs144850202; hg19: chr1-64027454;