4-146707504-G-C

Variant names:

• chr4-146707504-G-C
• rs201238305
• NM_031956.4:c.1378C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031956.4(TTC29):​c.1378C>G​(p.Arg460Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R460C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TTC29 NM_031956.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spermatogenic failure 42

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04192567).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031956.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC29	NM_031956.4	MANE Select	c.1378C>G	p.Arg460Gly	missense	Exon 12 of 13	NP_114162.2	Q8NA56-1
	TTC29	NM_001300761.4		c.1456C>G	p.Arg486Gly	missense	Exon 13 of 14	NP_001287690.1	G5E9Z5
	TTC29	NM_001317806.3		c.1375C>G	p.Arg459Gly	missense	Exon 12 of 13	NP_001304735.1	E7EQ14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC29	ENST00000325106.9	TSL:1 MANE Select	c.1378C>G	p.Arg460Gly	missense	Exon 12 of 13	ENSP00000316740.4	Q8NA56-1
	TTC29	ENST00000508306.5	TSL:1	n.*440C>G		non_coding_transcript_exon	Exon 13 of 14	ENSP00000422648.1	E7EQZ6
	TTC29	ENST00000508306.5	TSL:1	n.*440C>G		3_prime_UTR	Exon 13 of 14	ENSP00000422648.1	E7EQZ6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457962 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725326

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110536

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.19
DANN	Benign	0.66
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.047
Sift	Benign	0.30	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.081
MutPred		0.29		Gain of glycosylation at S484 (P = 0.0098)
MVP		0.10
MPC		0.016
ClinPred		0.23	T
GERP RS		-3.9
Varity_R		0.087
gMVP		0.077
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs201238305; hg19: chr4-147628656;