22-43537477-C-A

Position:

• chr22-43537477-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_022785.4(EFCAB6):​c.3948G>T​(p.Arg1316Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,614,126 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (43 hom.)
• Consequence: EFCAB6 NM_022785.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.850

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008342981).
• BP6: Variant 22-43537477-C-A is Benign according to our data. Variant chr22-43537477-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2653268.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFCAB6	NM_022785.4	c.3948G>T	p.Arg1316Ser	missense_variant	29/32	ENST00000262726.12	NP_073622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFCAB6	ENST00000262726.12	c.3948G>T	p.Arg1316Ser	missense_variant	29/32	2	NM_022785.4	ENSP00000262726	P1
EFCAB6	ENST00000396231.6	c.3492G>T	p.Arg1164Ser	missense_variant	27/30	1		ENSP00000379533
EFCAB6	ENST00000461800.5	n.585G>T		non_coding_transcript_exon_variant	4/7	1
EFCAB6-AS1	ENST00000656483.1	n.248+18880C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 845 AN: 152132 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00772

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00582 AC: 1463 AN: 251458 Hom.: 9 AF XY: 0.00594 AC XY: 807 AN XY: 135906

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.00767

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00545 AC: 7969 AN: 1461876 Hom.: 43 Cov.: 30 AF XY: 0.00549 AC XY: 3996 AN XY: 727240

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00241

Gnomad4 ASJ exome AF: 0.00555

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.0167

Gnomad4 NFE exome AF: 0.00573

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.00555 AC: 845 AN: 152250 Hom.: 5 Cov.: 32 AF XY: 0.00603 AC XY: 449 AN XY: 74440

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.00772

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00641 Hom.: 8

Bravo AF: 0.00420

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00581 AC: 706

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00758

EpiControl AF: 0.00682

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

EFCAB6: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0025	.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	.;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.072
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.32	.;B
Vest4		0.17
MutPred		0.74		.;Loss of MoRF binding (P = 0.0392);
MVP		0.36
MPC		0.076
ClinPred		0.023	T
GERP RS		4.7
Varity_R		0.14
gMVP		0.37

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: rs143251330; hg19: chr22-43933357; COSMIC: COSV99034679; COSMIC: COSV99034679;