chr8-30836810-C-T

Variant names:

• chr8-30836810-C-T
• rs146619272
• NM_001350162.2:c.9474G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_001350162.2(TEX15):​c.9474G>A​(p.Trp3158*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000557 in 1,600,142 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: TEX15 NM_001350162.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 1.69

Genes affected

TEX15 (HGNC:11738): (testis expressed 15, meiosis and synapsis associated) This gene encodes a protein that is required for DNA double-strand break repair, chromosome synapsis, and meiotic recombination in spermatocytes. Male mice with a knockout of the orthologous gene are viable but sterile. Loss-of-function mutations in the orthologous mouse gene cause early meiotic arrest in spermatocytes, before the mid-pachytene stage. Naturally occurring mutations in this gene are associated with nonobstructive azoospermia. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00473 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEX15	NM_001350162.2	c.9474G>A	p.Trp3158*	stop_gained	Exon 10 of 11	ENST00000643185.2	NP_001337091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEX15	ENST00000643185.2	c.9474G>A	p.Trp3158*	stop_gained	Exon 10 of 11		NM_001350162.2	ENSP00000493555.1
TEX15	ENST00000256246.5	c.8325G>A	p.Trp2775*	stop_gained	Exon 3 of 4	1		ENSP00000256246.2
TEX15	ENST00000638951.1	c.9486G>A	p.Trp3162*	stop_gained	Exon 9 of 10	5		ENSP00000492713.1

Frequencies

GnomAD3 genomes AF: 0.000776 AC: 118 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00720

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000889 AC: 214 AN: 240764 AF XY: 0.000985

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00602

Gnomad NFE exome AF: 0.000754

Gnomad OTH exome AF: 0.000687

GnomAD4 exome AF: 0.000534 AC: 773 AN: 1448178 Hom.: 3 Cov.: 32 AF XY: 0.000552 AC XY: 397 AN XY: 719428

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32822

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 42498

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25254

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39586

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 83594

Gnomad4 FIN exome AF: 0.00571 AC: 303 AN: 53024

Gnomad4 NFE exome AF: 0.000412 AC: 456 AN: 1105956

Gnomad4 Remaining exome AF: 0.000234 AC: 14 AN: 59748

GnomAD4 genome AF: 0.000776 AC: 118 AN: 151964 Hom.: 0 Cov.: 32 AF XY: 0.00104 AC XY: 77 AN XY: 74206

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00720 AC: 0.00719561 AN: 0.00719561

Gnomad4 NFE AF: 0.000618 AC: 0.000617756 AN: 0.000617756

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000665 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000700 AC: 85

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TEX15: PM2 -

Jun 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spermatogenic failure 25 Pathogenic:1

Feb 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.63	D
Vest4		0.21
GERP RS		2.6
Mutation Taster		=102/98	polymorphism

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: rs146619272; hg19: chr8-30694326; COSMIC: COSV56353897;