chr17-80415731-G-T

Position:

• chr17-80415731-G-T

Variant summary

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

The NM_173627.5(ENDOV):​c.138G>T​(p.Gln46His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000014 (0 hom.)
• Consequence: ENDOV NM_173627.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56

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]

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=0.16603297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENDOV	NM_173627.5	c.138G>T	p.Gln46His	missense_variant	2/10	ENST00000518137.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENDOV	ENST00000518137.6	c.138G>T	p.Gln46His	missense_variant	2/10	2	NM_173627.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456440 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724070

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

May 21, 2024

The c.138G>T (p.Q46H) alteration is located in exon 2 (coding exon 2) of the ENDOV gene. This alteration results from a G to T substitution at nucleotide position 138, causing the glutamine (Q) at amino acid position 46 to be replaced by a histidine (H). 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	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.025	T;.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.50	N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.26
MutPred		0.53		Loss of stability (P = 0.124);Loss of stability (P = 0.124);Loss of stability (P = 0.124);Loss of stability (P = 0.124);
MVP		0.18
MPC		0.023
ClinPred		0.11	T
GERP RS		0.50
Varity_R		0.29
gMVP		0.52

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: rs886858742; hg19: chr17-78389531;