chr9-137309658-T-C

Position:

• chr9-137309658-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017820.5(EXD3):​c.2227A>G​(p.Met743Val) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXD3 NM_017820.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.126

Genes affected

EXD3 (HGNC:26023): (exonuclease 3'-5' domain containing 3) Predicted to enable 3'-5' exonuclease activity. Predicted to be involved in nucleic acid phosphodiester bond hydrolysis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.159186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXD3	NM_017820.5	c.2227A>G	p.Met743Val	missense_variant	20/22	ENST00000340951.9	NP_060290.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXD3	ENST00000340951.9	c.2227A>G	p.Met743Val	missense_variant	20/22	1	NM_017820.5	ENSP00000340474.4
EXD3	ENST00000491734.6	n.*1334A>G		non_coding_transcript_exon_variant	14/15	1		ENSP00000435830.1
EXD3	ENST00000491734	n.*1159A>G		3_prime_UTR_variant	14/15	1		ENSP00000435830.1
EXD3	ENST00000487745.5	n.1555A>G		non_coding_transcript_exon_variant	10/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Sep 26, 2024

The c.2227A>G (p.M743V) alteration is located in exon 20 (coding exon 19) of the EXD3 gene. This alteration results from a A to G substitution at nucleotide position 2227, causing the methionine (M) at amino acid position 743 to be replaced by a valine (V). 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	Benign	0.33
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.49
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.56	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.14
Sift	Uncertain	0.023	D
Sift4G	Benign	0.13	T
Polyphen		0.80	P
Vest4		0.31
MutPred		0.49		Gain of methylation at K744 (P = 0.0197);
MVP		0.18
MPC		0.21
ClinPred		0.29	T
GERP RS		-0.42
Varity_R		0.12
gMVP		0.77

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-140204110;