chr17-58569261-C-T

Position:

• chr17-58569261-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PVS1_Moderate PP3_Moderate BP6 BS1 BS2

The NM_031272.5(TEX14):​c.3818-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00061 in 1,613,678 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: TEX14 NM_031272.5 splice_acceptor
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0550

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.015610652 fraction of the gene. Cryptic splice site detected, with MaxEntScore 2.6, offset of 3, new splice context is: tcttttttaaaaactaatAGaag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• BP6: Variant 17-58569261-C-T is Benign according to our data. Variant chr17-58569261-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 746683.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00225 (342/152306) while in subpopulation AFR AF= 0.00664 (276/41566). AF 95% confidence interval is 0.006. There are 2 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TEX14	NM_031272.5	c.3818-1G>A		splice_acceptor_variant		ENST00000349033.10
TEX14	NM_001201457.2	c.3956-1G>A		splice_acceptor_variant
TEX14	NM_198393.4	c.3938-1G>A		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TEX14	ENST00000349033.10	c.3818-1G>A		splice_acceptor_variant		5	NM_031272.5	A2

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152188 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000898 AC: 225 AN: 250572 Hom.: 2 AF XY: 0.000672 AC XY: 91 AN XY: 135508

Gnomad AFR exome AF: 0.00679

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.000440 AC: 643 AN: 1461372 Hom.: 1 Cov.: 30 AF XY: 0.000398 AC XY: 289 AN XY: 726986

Gnomad4 AFR exome AF: 0.00646

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152306 Hom.: 2 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74482

Gnomad4 AFR AF: 0.00664

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000842 Hom.: 0

Bravo AF: 0.00297

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spermatogenic failure 23 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Jan 08, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.84
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.53	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -18
DS_AL_spliceai		0.87		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs55759912; hg19: chr17-56646622;