chr17-80423537-C-T

Position:

• chr17-80423537-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173627.5(ENDOV):​c.421C>T​(p.His141Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0018 in 1,553,346 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0031 (6 hom., cov: 34)
  • Exomes 𝑓: 0.0017 (27 hom.)
• Consequence: ENDOV NM_173627.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.61

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 Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, FATHMM_MKL, MutationAssessor, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009590507).
• BP6: Variant 17-80423537-C-T is Benign according to our data. Variant chr17-80423537-C-T is described in ClinVar as [Benign]. Clinvar id is 668760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0031 (472/152292) while in subpopulation AMR AF= 0.0175 (268/15308). AF 95% confidence interval is 0.0158. There are 6 homozygotes in gnomad4. There are 286 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENDOV	NM_173627.5	c.421C>T	p.His141Tyr	missense_variant	5/10	ENST00000518137.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENDOV	ENST00000518137.6	c.421C>T	p.His141Tyr	missense_variant	5/10	2	NM_173627.5	P1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152174 Hom.: 6 Cov.: 34

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00542

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00769 AC: 1228 AN: 159706 Hom.: 19 AF XY: 0.00600 AC XY: 507 AN XY: 84560

Gnomad AFR exome AF: 0.000362

Gnomad AMR exome AF: 0.0379

Gnomad ASJ exome AF: 0.00620

Gnomad EAS exome AF: 0.00385

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00653

Gnomad NFE exome AF: 0.000366

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00166 AC: 2331 AN: 1401054 Hom.: 27 Cov.: 35 AF XY: 0.00155 AC XY: 1073 AN XY: 691248

Gnomad4 AFR exome AF: 0.000315

Gnomad4 AMR exome AF: 0.0344

Gnomad4 ASJ exome AF: 0.00599

Gnomad4 EAS exome AF: 0.00521

Gnomad4 SAS exome AF: 0.00149

Gnomad4 FIN exome AF: 0.00546

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.00241

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152292 Hom.: 6 Cov.: 34 AF XY: 0.00384 AC XY: 286 AN XY: 74460

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00543

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00734

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00448

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000373 AC: 3

ExAC AF: 0.00259 AC: 278

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.;T;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
MetaRNN	Benign	0.0096	T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.6	H;.;.;.;.;.;.
MutationTaster	Benign	0.90	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.9	D;D;D;.;.;.;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.92
MVP		0.44
MPC		0.20
ClinPred		0.057	T
GERP RS		3.5
Varity_R		0.99
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41299812; hg19: chr17-78397337; COSMIC: COSV99073621; COSMIC: COSV99073621;