chr15-41189996-C-T

Variant names:

• chr15-41189996-C-T
• rs1372676201
• NM_001286441.2:c.997G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001286441.2(EXD1):​c.997G>A​(p.Val333Met) variant causes a missense change. 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: 32)
• Consequence: EXD1 NM_001286441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.60
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

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.997G>A	p.Val333Met	missense	Exon 11 of 12	NP_001273370.1	Q8NHP7-3
	EXD1	NM_001385036.1		c.928G>A	p.Val310Met	missense	Exon 10 of 11	NP_001371965.1
	EXD1	NM_152596.4		c.823G>A	p.Val275Met	missense	Exon 9 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.997G>A	p.Val333Met	missense	Exon 11 of 12	ENSP00000415056.2	Q8NHP7-3
	EXD1	ENST00000314992.9	TSL:1	c.823G>A	p.Val275Met	missense	Exon 9 of 10	ENSP00000321029.5	Q8NHP7-1
	EXD1	ENST00000558881.1	TSL:2	n.375G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.056	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.59		Gain of disorder (P = 0.0263)
MVP		0.49
MPC		0.23
ClinPred		0.92	D
GERP RS		6.1
Varity_R		0.23
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1372676201; hg19: chr15-41482194;