17-80421910-T-G

Position:

• chr17-80421910-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_173627.5(ENDOV):​c.311T>G​(p.Leu104Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,050 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ENDOV NM_173627.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.48

Genes affected

ENDOV (HGNC:26640): (endonuclease V) Enables DNA binding activity; endoribonuclease activity, producing 5'-phosphomonoesters; and single-stranded RNA binding activity. Predicted to be involved in DNA repair. Located in cytoplasmic stress granule and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ENDOV (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENDOV	NM_173627.5	c.311T>G	p.Leu104Trp	missense_variant	3/10	ENST00000518137.6	NP_775898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENDOV	ENST00000518137.6	c.311T>G	p.Leu104Trp	missense_variant	3/10	2	NM_173627.5	ENSP00000429190.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459050 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725618

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

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

Dec 02, 2024

The c.311T>G (p.L104W) alteration is located in exon 3 (coding exon 3) of the ENDOV gene. This alteration results from a T to G substitution at nucleotide position 311, causing the leucine (L) at amino acid position 104 to be replaced by a tryptophan (W). 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	0.73
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T;.;T;.;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.9	D;D;.;.;.;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;D;.;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.77
MutPred		0.72		Loss of stability (P = 0.1063);.;.;.;.;.;
MVP		0.69
MPC		0.22
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.84

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: rs2082088787; hg19: chr17-78395710;