Genetic Variant NM_031956.4:c.800-1G>A (chr4-146867584-C-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_031956.4(TTC29):c.800-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000371 in 1,463,458 control chromosomes in the GnomAD database, including 1 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

TTC29
NM_031956.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.61

Variant links:

Genes affected

TTC29 (HGNC:29936): (tetratricopeptide repeat domain 29) Involved in cilium movement and cilium organization. Located in sperm flagellum. Implicated in spermatogenic failure 42. [provided by Alliance of Genome Resources, Apr 2022]

TTC29 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5, offset of 1, new splice context is: ttttacatcttcacttcaAGaag. Cryptic site results in frameshift 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 4-146867584-C-T is Pathogenic according to our data. Variant chr4-146867584-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3350480.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC29	NM_031956.4 link	c.800-1G>A		splice_acceptor_variant, intron_variant	Intron 7 of 12	ENST00000325106.9	NP_114162.2	Q8NA56-1A0A140VK62Q8TC83

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTC29	ENST00000325106.9 link	c.800-1G>A	splice_acceptor_variant, intron_variant	Intron 7 of 12	1	NM_031956.4	ENSP00000316740.4	Q8NA56-1
TTC29	ENST00000508306.5 link	n.800-1G>A	splice_acceptor_variant, intron_variant	Intron 7 of 13	1		ENSP00000422648.1	E7EQZ6
TTC29	ENST00000513335.5 link	c.878-1G>A	splice_acceptor_variant, intron_variant	Intron 8 of 13	2		ENSP00000423505.1	G5E9Z5
TTC29	ENST00000504425.5 link	c.800-1G>A	splice_acceptor_variant, intron_variant	Intron 7 of 12	5		ENSP00000425778.1	E7EQ14

Frequencies

GnomAD3 genomes

AF:

0.000257

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000173

AC:

AN:

144322

Hom.:

AF XY:

0.000143

AC XY:

AN XY:

77150

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.000451

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000258

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000384

AC:

504

AN:

1311334

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

229

AN XY:

650012

show subpopulations

Gnomad4 AFR exome

AF:

0.000104

Gnomad4 AMR exome

AF:

0.000384

Gnomad4 ASJ exome

AF:

0.0000430

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000205

Gnomad4 NFE exome

AF:

0.000477

Gnomad4 OTH exome

AF:

0.0000370

GnomAD4 genome

AF:

0.000256

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000333

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.000111

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TTC29-related condition

Pathogenic:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TTC29 c.878-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.043% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice acceptor site in TTC29 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.89

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: -2

DS_AL_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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over