4-146833843-C-T

Position:

• chr4-146833843-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (21 hom.)
• Consequence: TTC29 NM_031956.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.82

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]

LOC105377474 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013542175).
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC29	NM_031956.4	c.940G>A	p.Gly314Arg	missense_variant	9/13	ENST00000325106.9	NP_114162.2
LOC105377474	XR_939314.2			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC29	ENST00000325106.9	c.940G>A	p.Gly314Arg	missense_variant	9/13	1	NM_031956.4	ENSP00000316740	P4
TTC29	ENST00000508306.5	c.940G>A	p.Gly314Arg	missense_variant, NMD_transcript_variant	9/14	1		ENSP00000422648
TTC29	ENST00000513335.5	c.1018G>A	p.Gly340Arg	missense_variant	10/14	2		ENSP00000423505
TTC29	ENST00000504425.5	c.940G>A	p.Gly314Arg	missense_variant	9/13	5		ENSP00000425778	A1

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

GnomAD3 exomes AF: 0.00260 AC: 646 AN: 248264 Hom.: 1 AF XY: 0.00245 AC XY: 330 AN XY: 134670

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 SAS exome AF: 0.000850

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

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00379

Gnomad4 NFE exome AF: 0.00519

Gnomad4 OTH exome AF: 0.00252

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

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00528

Gnomad4 NFE AF: 0.00469

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00394 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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.5	.;M;.
MutationTaster	Benign	0.92	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.054	T;D;D
Sift4G	Benign	0.38	T;T;T
Polyphen		0.83	P;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs143005058; hg19: chr4-147754995;