15-41184089-T-C

Variant names:

• chr15-41184089-T-C
• rs185697361
• NM_001286441.2:c.1561A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001286441.2(EXD1):​c.1561A>G​(p.Lys521Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,614,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000059 (1 hom.)
• Consequence: EXD1 NM_001286441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.838
• Publications: 0 publications found

Genes affected

EXD1 (HGNC:28507): (exonuclease 3'-5' domain containing 1) Predicted to enable RNA binding activity and protein homodimerization activity. Predicted to be involved in gene silencing by RNA and piRNA metabolic process. Predicted to be located in P granule. Predicted to be part of PET complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015872002).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286441.2. 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
	EXD1	NM_001286441.2	MANE Select	c.1561A>G	p.Lys521Glu	missense	Exon 12 of 12	NP_001273370.1	Q8NHP7-3
	EXD1	NM_001385036.1		c.1492A>G	p.Lys498Glu	missense	Exon 11 of 11	NP_001371965.1
	EXD1	NM_152596.4		c.1387A>G	p.Lys463Glu	missense	Exon 10 of 10	NP_689809.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXD1	ENST00000458580.7	TSL:2 MANE Select	c.1561A>G	p.Lys521Glu	missense	Exon 12 of 12	ENSP00000415056.2	Q8NHP7-3
	EXD1	ENST00000314992.9	TSL:1	c.1387A>G	p.Lys463Glu	missense	Exon 10 of 10	ENSP00000321029.5	Q8NHP7-1
	EXD1	ENST00000558881.1	TSL:2	n.939A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000119 AC: 30 AN: 251424 AF XY: 0.0000957

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461884 Hom.: 1 Cov.: 60 AF XY: 0.0000770 AC XY: 56 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39698

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.000381 AC: 23 AN: 60396

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5194

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T
Eigen	Benign	0.045
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.84
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.024	D
Polyphen		0.73	P
Vest4		0.13
MVP		0.19
MPC		0.037
ClinPred		0.057	T
GERP RS		5.2
Varity_R		0.17
gMVP		0.28
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs185697361; hg19: chr15-41476287;