chr4-146867532-T-C

Variant names:

• chr4-146867532-T-C
• rs369571582
• NM_031956.4:c.851A>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_031956.4(TTC29):​c.851A>G​(p.His284Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000224 in 1,554,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: TTC29 NM_031956.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.69

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22488242).
• BP6: Variant 4-146867532-T-C is Benign according to our data. Variant chr4-146867532-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2655113.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC29	NM_031956.4	c.851A>G	p.His284Arg	missense_variant	Exon 8 of 13	ENST00000325106.9	NP_114162.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC29	ENST00000325106.9	c.851A>G	p.His284Arg	missense_variant	Exon 8 of 13	1	NM_031956.4	ENSP00000316740.4
TTC29	ENST00000508306.5	n.851A>G		non_coding_transcript_exon_variant	Exon 8 of 14	1		ENSP00000422648.1
TTC29	ENST00000513335.5	c.929A>G	p.His310Arg	missense_variant	Exon 9 of 14	2		ENSP00000423505.1
TTC29	ENST00000504425.5	c.851A>G	p.His284Arg	missense_variant	Exon 8 of 13	5		ENSP00000425778.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000199 AC: 39 AN: 195712 Hom.: 0 AF XY: 0.000171 AC XY: 18 AN XY: 105468

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00158

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000170

Gnomad FIN exome AF: 0.000155

Gnomad NFE exome AF: 0.000198

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.000226 AC: 317 AN: 1402390 Hom.: 0 Cov.: 27 AF XY: 0.000243 AC XY: 169 AN XY: 694480

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000523

Gnomad4 ASJ exome AF: 0.00129

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.000296

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.000208

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000629 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000192 AC: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.851A>G (p.H284R) alteration is located in exon 8 (coding exon 6) of the TTC29 gene. This alteration results from a A to G substitution at nucleotide position 851, causing the histidine (H) at amino acid position 284 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTC29: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	.;T;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.6	.;M;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.3	D;D;.;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.024	D;D;.;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.96	D;D;.;D
Vest4		0.40
MVP		0.77
MPC		0.036
ClinPred		0.41	T
GERP RS		5.5
Varity_R		0.37
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs369571582; hg19: chr4-147788684; COSMIC: COSV57277045;