3-38524014-T-G

Position:

• chr3-38524014-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005107.4(EXOG):​c.759T>G​(p.Asn253Lys) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EXOG NM_005107.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.569

Genes affected

EXOG (HGNC:3347): (exo/endonuclease G) This gene encodes an endo/exonuclease with 5'-3' exonuclease activity. The encoded enzyme catalyzes the hydrolysis of ester linkages at the 5' end of a nucleic acid chain. This enzyme is localized to the mitochondria and may play a role in programmed cell death. Alternatively spliced transcript variants have been described. A pseudogene exists on chromosome 18. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOG	NM_005107.4	c.759T>G	p.Asn253Lys	missense_variant	6/6	ENST00000287675.10	NP_005098.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOG	ENST00000287675.10	c.759T>G	p.Asn253Lys	missense_variant	6/6	1	NM_005107.4	ENSP00000287675.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Aug 21, 2024

The c.759T>G (p.N253K) alteration is located in exon 6 (coding exon 6) of the EXOG gene. This alteration results from a T to G substitution at nucleotide position 759, causing the asparagine (N) at amino acid position 253 to be replaced by a lysine (K). 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	0.98
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.
Eigen	Benign	0.016
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.097	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.79		Gain of methylation at N253 (P = 0.0115);.;
MVP		0.19
MPC		0.69
ClinPred		1.0	D
GERP RS		-6.3
Varity_R		0.94
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-38565505;