NM_022785.4:c.3948G>T

Variant names:

• chr22-43537477-C-A
• rs143251330
• NM_022785.4:c.3948G>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 2653268.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022785.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFCAB6	NM_022785.4	MANE Select	c.3948G>T	p.Arg1316Ser	missense	Exon 29 of 32	NP_073622.2
	EFCAB6	NM_198856.3		c.3492G>T	p.Arg1164Ser	missense	Exon 27 of 30	NP_942153.1	Q5THR3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFCAB6	ENST00000262726.12	TSL:2 MANE Select	c.3948G>T	p.Arg1316Ser	missense	Exon 29 of 32	ENSP00000262726.7	Q5THR3-1
	EFCAB6	ENST00000396231.6	TSL:1	c.3492G>T	p.Arg1164Ser	missense	Exon 27 of 30	ENSP00000379533.2	Q5THR3-2
	EFCAB6	ENST00000461800.5	TSL:1	n.585G>T		non_coding_transcript_exon	Exon 4 of 7

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

GnomAD2 exomes AF: 0.00582 AC: 1463 AN: 251458 AF XY: 0.00594

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 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

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00241 AC: 108 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00555 AC: 145 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000568 AC: 49 AN: 86256

European-Finnish (FIN) AF: 0.0167 AC: 894 AN: 53414

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5766

European-Non Finnish (NFE) AF: 0.00573 AC: 6374 AN: 1112006

Other (OTH) AF: 0.00523 AC: 316 AN: 60396

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

African (AFR) AF: 0.000987 AC: 41 AN: 41554

American (AMR) AF: 0.00353 AC: 54 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4798

European-Finnish (FIN) AF: 0.0166 AC: 176 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00772 AC: 525 AN: 68010

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00635 Hom.: 12

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.85
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.072
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	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
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

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