chr9-137309637-T-A

Position:

• chr9-137309637-T-A

Variant summary

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

The NM_017820.5(EXD3):​c.2248A>T​(p.Ser750Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,564 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: EXD3 NM_017820.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.416

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=0.16572797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXD3	NM_017820.5	c.2248A>T	p.Ser750Cys	missense_variant	20/22	ENST00000340951.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXD3	ENST00000340951.9	c.2248A>T	p.Ser750Cys	missense_variant	20/22	1	NM_017820.5	P1
EXD3	ENST00000491734.6	c.*1355A>T		3_prime_UTR_variant, NMD_transcript_variant	14/15	1
EXD3	ENST00000487745.5	n.1576A>T		non_coding_transcript_exon_variant	10/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000229 AC: 4 AN: 174732 Hom.: 0 AF XY: 0.0000215 AC XY: 2 AN XY: 93190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000323

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000425 AC: 6 AN: 1410564 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 696930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000163

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.082
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.058	T
Polyphen		0.98	D
Vest4		0.18
MutPred		0.49		Loss of disorder (P = 0.0377);
MVP		0.32
MPC		0.29
ClinPred		0.13	T
GERP RS		0.88
Varity_R		0.079
gMVP		0.48

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: rs1489281737; hg19: chr9-140204089;