14-69209618-A-G

Position:

• chr14-69209618-A-G

Variant summary

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

The NM_001193360.2(EXD2):​c.148A>G​(p.Ser50Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,398,308 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: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: EXD2 NM_001193360.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.852

Genes affected

EXD2 (HGNC:20217): (exonuclease 3'-5' domain containing 2) Enables 3'-5' exonuclease activity; metal ion binding activity; and protein homodimerization activity. Involved in nucleic acid metabolic process. Located in intermediate filament cytoskeleton; mitochondrial outer membrane; and site of DNA damage. [provided by Alliance of Genome Resources, Apr 2022]

GALNT16-AS1 (HGNC:55435): (GALNT16 and EXD2 antisense RNA 1)

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=0.049520493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXD2	NM_001193360.2	c.148A>G	p.Ser50Gly	missense_variant	3/10	ENST00000685843.1	NP_001180289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXD2	ENST00000685843.1	c.148A>G	p.Ser50Gly	missense_variant	3/10		NM_001193360.2	ENSP00000510642.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1398308 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689678

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Mar 02, 2023

The c.148A>G (p.S50G) alteration is located in exon 3 (coding exon 1) of the EXD2 gene. This alteration results from a A to G substitution at nucleotide position 148, causing the serine (S) at amino acid position 50 to be replaced by a glycine (G). 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	0.056
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.19
DANN	Benign	0.64
DEOGEN2	Benign	0.0023	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.30	.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.20	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.12
Sift	Benign	0.48	T;T
Sift4G	Benign	0.40	T;T
Vest4		0.069
MutPred		0.24		Gain of catalytic residue at P54 (P = 8e-04);Gain of catalytic residue at P54 (P = 8e-04);
MVP		0.17
MPC		0.13
ClinPred		0.027	T
GERP RS		-4.8
Varity_R		0.022
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1368124558; hg19: chr14-69676335;