NM_031956.4:c.851A>G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. 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
• Publications: 2 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 -3 ACMG points.

• 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 VariationId is 2655113.

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.851A>G	p.His284Arg	missense	Exon 8 of 13	NP_114162.2	Q8NA56-1
	TTC29	NM_001300761.4		c.929A>G	p.His310Arg	missense	Exon 9 of 14	NP_001287690.1	G5E9Z5
	TTC29	NM_001317806.3		c.851A>G	p.His284Arg	missense	Exon 8 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.851A>G	p.His284Arg	missense	Exon 8 of 13	ENSP00000316740.4	Q8NA56-1
	TTC29	ENST00000508306.5	TSL:1	n.851A>G		non_coding_transcript_exon	Exon 8 of 14	ENSP00000422648.1	E7EQZ6
	TTC29	ENST00000513335.5	TSL:2	c.929A>G	p.His310Arg	missense	Exon 9 of 14	ENSP00000423505.1	G5E9Z5

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

GnomAD2 exomes AF: 0.000199 AC: 39 AN: 195712 AF XY: 0.000171

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 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

African (AFR) AF: 0.00 AC: 0 AN: 31716

American (AMR) AF: 0.0000523 AC: 2 AN: 38252

Ashkenazi Jewish (ASJ) AF: 0.00129 AC: 32 AN: 24784

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37300

South Asian (SAS) AF: 0.000278 AC: 21 AN: 75672

European-Finnish (FIN) AF: 0.000296 AC: 15 AN: 50658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.000217 AC: 234 AN: 1080820

Other (OTH) AF: 0.000208 AC: 12 AN: 57588

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

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.7
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.015	D
Polyphen		0.96	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
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

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