Genetic Variant TEX14:c.3818-1G>A (chr17-58569261-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2

The NM_031272.5(TEX14):c.3818-1G>A variant causes a splice acceptor, intron 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, intron

Scores

Splicing: ADA: 0.9998

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.0550

Publications

3 publications found

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]

TEX14 links:

SEPTIN4-AS1 (HGNC:51345): (SEPTIN4 antisense RNA 1)

SEPTIN4-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.015840221 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.

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 VariationId is 746683.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 342 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031272.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TEX14	NM_031272.5	MANE Select	c.3818-1G>A	splice_acceptor intron	N/A	NP_112562.3
TEX14	NM_001201457.2		c.3956-1G>A	splice_acceptor intron	N/A	NP_001188386.1	Q8IWB6-1
TEX14	NM_198393.4		c.3938-1G>A	splice_acceptor intron	N/A	NP_938207.2	Q8IWB6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TEX14	ENST00000349033.10	TSL:5 MANE Select	c.3818-1G>A	splice_acceptor intron	N/A	ENSP00000268910.8	Q8IWB6-3
TEX14	ENST00000240361.12	TSL:1	c.3956-1G>A	splice_acceptor intron	N/A	ENSP00000240361.8	Q8IWB6-1
TEX14	ENST00000389934.7	TSL:1	c.3938-1G>A	splice_acceptor intron	N/A	ENSP00000374584.3	Q8IWB6-2

Frequencies

GnomAD3 genomes

AF:

0.00217

AC:

330

AN:

152188

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000898

AC:

225

AN:

250572

AF XY:

0.000672

show subpopulations

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 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.:

Cov.:

AF XY:

0.000398

AC XY:

289

AN XY:

726986

show subpopulations

African (AFR)

AF:

0.00646

AC:

216

AN:

33460

American (AMR)

AF:

0.00159

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000209

AC:

232

AN:

1111650

Other (OTH)

AF:

0.00103

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00225

AC:

342

AN:

152306

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00664

AC:

276

AN:

41566

American (AMR)

AF:

0.00176

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68018

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000851

Hom.:

Bravo

AF:

0.00297

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000857

AC:

104

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000475

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Spermatogenic failure 23 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.84

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.53

PhyloP100

-0.055

GERP RS

1.1

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over