chr4-146833843-C-T

Variant names:

• chr4-146833843-C-T
• rs143005058
• NM_031956.4:c.940G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_031956.4(TTC29):​c.940G>A​(p.Gly314Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 1,613,290 control chromosomes in the GnomAD database, including 23 homozygotes. 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 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (21 hom.)
• Consequence: TTC29 NM_031956.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.82
• Publications: 5 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

LOC105377474 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013542175).
• BP6: Variant 4-146833843-C-T is Benign according to our data. Variant chr4-146833843-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1335566.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00286 (435/152262) while in subpopulation NFE AF = 0.00469 (319/68030). AF 95% confidence interval is 0.00427. There are 2 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.940G>A	p.Gly314Arg	missense	Exon 9 of 13	NP_114162.2	Q8NA56-1
	TTC29	NM_001300761.4		c.1018G>A	p.Gly340Arg	missense	Exon 10 of 14	NP_001287690.1	G5E9Z5
	TTC29	NM_001317806.3		c.940G>A	p.Gly314Arg	missense	Exon 9 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.940G>A	p.Gly314Arg	missense	Exon 9 of 13	ENSP00000316740.4	Q8NA56-1
	TTC29	ENST00000508306.5	TSL:1	n.940G>A		non_coding_transcript_exon	Exon 9 of 14	ENSP00000422648.1	E7EQZ6
	TTC29	ENST00000513335.5	TSL:2	c.1018G>A	p.Gly340Arg	missense	Exon 10 of 14	ENSP00000423505.1	G5E9Z5

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00528

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00469

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00260 AC: 646 AN: 248264 AF XY: 0.00245

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00414

Gnomad NFE exome AF: 0.00429

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00431 AC: 6298 AN: 1461028 Hom.: 21 Cov.: 30 AF XY: 0.00420 AC XY: 3056 AN XY: 726794

African (AFR) AF: 0.000538 AC: 18 AN: 33452

American (AMR) AF: 0.000850 AC: 38 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26114

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39632

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86236

European-Finnish (FIN) AF: 0.00379 AC: 202 AN: 53334

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00519 AC: 5768 AN: 1111476

Other (OTH) AF: 0.00252 AC: 152 AN: 60330

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152262 Hom.: 2 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74436

African (AFR) AF: 0.000626 AC: 26 AN: 41562

American (AMR) AF: 0.00157 AC: 24 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00528 AC: 56 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00469 AC: 319 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00369 Hom.: 1

Bravo AF: 0.00242

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000772 AC: 3

ESP6500EA AF: 0.00386 AC: 32

ExAC AF: 0.00236 AC: 285

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.8
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.61
Sift	Benign	0.054	T
Sift4G	Benign	0.38	T
Polyphen		0.83	P
Vest4		0.67
MutPred		0.67		Loss of methylation at R341 (P = 0.0455)
MVP		0.75
MPC		0.086
ClinPred		0.026	T
GERP RS		3.9
Varity_R		0.54
gMVP		0.66
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs143005058; hg19: chr4-147754995; COSMIC: COSV108853463;