15-41184546-G-C

Position:

• chr15-41184546-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286441.2(EXD1):​c.1104C>G​(p.Phe368Leu) 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. 13/21 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: EXD1 NM_001286441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0470

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06470147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXD1	NM_001286441.2	c.1104C>G	p.Phe368Leu	missense_variant	12/12	ENST00000458580.7	NP_001273370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXD1	ENST00000458580.7	c.1104C>G	p.Phe368Leu	missense_variant	12/12	2	NM_001286441.2	ENSP00000415056.2
EXD1	ENST00000314992.9	c.930C>G	p.Phe310Leu	missense_variant	10/10	1		ENSP00000321029.5
EXD1	ENST00000558881.1	n.482C>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Jan 30, 2024

The c.930C>G (p.F310L) alteration is located in exon 10 (coding exon 10) of the EXD1 gene. This alteration results from a C to G substitution at nucleotide position 930, causing the phenylalanine (F) at amino acid position 310 to be replaced by a leucine (L). 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	Pathogenic	0.71
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.0085	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.017
Sift	Benign	0.13	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0010	B;.
Vest4		0.12
MutPred		0.43		Gain of disorder (P = 0.0499);.;
MVP		0.11
MPC		0.032
ClinPred		0.18	T
GERP RS		0.75
Varity_R		0.047
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs377668115; hg19: chr15-41476744;