chr22-43540225-C-A

Position:

• chr22-43540225-C-A

Variant summary

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

The NM_022785.4(EFCAB6):​c.3781G>T​(p.Gly1261Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 33)
• Consequence: EFCAB6 NM_022785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

Genes affected

EFCAB6 (HGNC:24204): (EF-hand calcium binding domain 6) This gene encodes a protein which directly binds the oncogene DJ-1 and androgen receptor to form a ternary complex in cells. This binding protein recruits histone-deacetylase complexes in order to repress transcription activity of androgen receptor. This protein may also play a role in spermatogenesis and fertilization. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

EFCAB6-AS1 (HGNC:39999): (EFCAB6 antisense RNA 1)

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, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFCAB6	NM_022785.4	c.3781G>T	p.Gly1261Trp	missense_variant	28/32	ENST00000262726.12	NP_073622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFCAB6	ENST00000262726.12	c.3781G>T	p.Gly1261Trp	missense_variant	28/32	2	NM_022785.4	ENSP00000262726	P1
EFCAB6	ENST00000396231.6	c.3325G>T	p.Gly1109Trp	missense_variant	26/30	1		ENSP00000379533
EFCAB6	ENST00000461800.5	n.418G>T		non_coding_transcript_exon_variant	3/7	1
EFCAB6-AS1	ENST00000656483.1	n.249-18392C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 12, 2023

The c.3781G>T (p.G1261W) alteration is located in exon 28 (coding exon 26) of the EFCAB6 gene. This alteration results from a G to T substitution at nucleotide position 3781, causing the glycine (G) at amino acid position 1261 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	0.30
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.091
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;M
MutationTaster	Benign	0.78	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.57
MutPred		0.72		.;Loss of glycosylation at S1262 (P = 0.0464);
MVP		0.55
MPC		0.38
ClinPred		0.96	D
GERP RS		3.3
Varity_R		0.19
gMVP		0.28

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: rs200387757; hg19: chr22-43936105;