17-58559452-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_031272.5(TEX14):​c.4267+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,281,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TEX14
NM_031272.5 splice_donor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.23
Variant links:
Genes affected
TEX14 (HGNC:11737): (testis expressed 14, intercellular bridge forming factor) The protein encoded by this gene is necessary for intercellular bridges in germ cells, which are required for spermatogenesis. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.025252525 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.9, offset of 12, new splice context is: aatGTatgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-58559452-C-T is Pathogenic according to our data. Variant chr17-58559452-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3780705.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TEX14NM_031272.5 linkc.4267+1G>A splice_donor_variant, intron_variant Intron 30 of 31 ENST00000349033.10 NP_112562.3 Q8IWB6-3
TEX14NM_001201457.2 linkc.4405+1G>A splice_donor_variant, intron_variant Intron 31 of 32 NP_001188386.1 Q8IWB6-1
TEX14NM_198393.4 linkc.4387+1G>A splice_donor_variant, intron_variant Intron 31 of 32 NP_938207.2 Q8IWB6-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TEX14ENST00000349033.10 linkc.4267+1G>A splice_donor_variant, intron_variant Intron 30 of 31 5 NM_031272.5 ENSP00000268910.8 Q8IWB6-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
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:
0.000415
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000367
AC:
9
AN:
245090
Hom.:
0
AF XY:
0.0000679
AC XY:
9
AN XY:
132470
show subpopulations
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 SAS exome
AF:
0.000312
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000292
AC:
33
AN:
1129708
Hom.:
0
Cov.:
16
AF XY:
0.0000485
AC XY:
28
AN XY:
577270
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000265
Gnomad4 SAS exome
AF:
0.000375
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000613
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152288
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
ExAC
AF:
0.0000577
AC:
7

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1
Apr 18, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.95
D
GERP RS
5.0

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.65
Position offset: -11
DS_DL_spliceai
0.97
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752772371; hg19: chr17-56636813; API