22-43540131-G-T

Position:

• chr22-43540131-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022785.4(EFCAB6):​c.3875C>A​(p.Pro1292His) 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 benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EFCAB6 NM_022785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14843437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFCAB6	NM_022785.4	c.3875C>A	p.Pro1292His	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.3875C>A	p.Pro1292His	missense_variant	28/32	2	NM_022785.4	ENSP00000262726	P1
EFCAB6	ENST00000396231.6	c.3419C>A	p.Pro1140His	missense_variant	26/30	1		ENSP00000379533
EFCAB6	ENST00000461800.5	n.512C>A		non_coding_transcript_exon_variant	3/7	1
EFCAB6-AS1	ENST00000656483.1	n.249-18486G>T		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

Feb 21, 2024

The c.3875C>A (p.P1292H) alteration is located in exon 28 (coding exon 26) of the EFCAB6 gene. This alteration results from a C to A substitution at nucleotide position 3875, causing the proline (P) at amino acid position 1292 to be replaced by a histidine (H). 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	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0047	.;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.027
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.090	.;B
Vest4		0.36
MutPred		0.52		.;Loss of glycosylation at P1292 (P = 0.0167);
MVP		0.17
MPC		0.37
ClinPred		0.67	D
GERP RS		1.8
Varity_R		0.13
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-43936011;