4-146867584-C-T

Variant names:

• chr4-146867584-C-T
• rs373283697
• NM_031956.4:c.800-1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

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

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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.
• 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	c.800-1G>A		splice_acceptor_variant, intron_variant	Intron 7 of 12	ENST00000325106.9	NP_114162.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 152006 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000173 AC: 25 AN: 144322 AF XY: 0.000143

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 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.: 1 Cov.: 21 AF XY: 0.000352 AC XY: 229 AN XY: 650012

Gnomad4 AFR exome AF: 0.000104 AC: 3 AN: 28784

Gnomad4 AMR exome AF: 0.000384 AC: 11 AN: 28622

Gnomad4 ASJ exome AF: 0.0000430 AC: 1 AN: 23256

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35108

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 68094

Gnomad4 FIN exome AF: 0.0000205 AC: 1 AN: 48748

Gnomad4 NFE exome AF: 0.000477 AC: 486 AN: 1019284

Gnomad4 Remaining exome AF: 0.0000370 AC: 2 AN: 54064

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74372

Gnomad4 AFR AF: 0.000193 AC: 0.000192688 AN: 0.000192688

Gnomad4 AMR AF: 0.000197 AC: 0.000196618 AN: 0.000196618

Gnomad4 ASJ AF: 0.000288 AC: 0.000288351 AN: 0.000288351

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000397 AC: 0.000397094 AN: 0.000397094

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.000111 AC: 13

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.5
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs373283697; hg19: chr4-147788736; COSMIC: COSV57283297;