Genetic Variant TTC29:p.Ala274Glu (chr4-146867562-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_031956.4(TTC29):c.821C>A(p.Ala274Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,379,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A274V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TTC29
NM_031956.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.07

Publications

0 publications found

Variant links:

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

TTC29 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4115838).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC29	NM_031956.4	MANE Select	c.821C>A	p.Ala274Glu	missense	Exon 8 of 13	NP_114162.2	Q8NA56-1
TTC29	NM_001300761.4		c.899C>A	p.Ala300Glu	missense	Exon 9 of 14	NP_001287690.1	G5E9Z5
TTC29	NM_001317806.3		c.821C>A	p.Ala274Glu	missense	Exon 8 of 13	NP_001304735.1	E7EQ14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC29	ENST00000325106.9	TSL:1 MANE Select	c.821C>A	p.Ala274Glu	missense	Exon 8 of 13	ENSP00000316740.4	Q8NA56-1
TTC29	ENST00000508306.5	TSL:1	n.821C>A		non_coding_transcript_exon	Exon 8 of 14	ENSP00000422648.1	E7EQZ6
TTC29	ENST00000513335.5	TSL:2	c.899C>A	p.Ala300Glu	missense	Exon 9 of 14	ENSP00000423505.1	G5E9Z5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000218

AC:

AN:

1379112

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

682464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30904

American (AMR)

AF:

0.00

AC:

AN:

35418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24460

East Asian (EAS)

AF:

0.00

AC:

AN:

36312

South Asian (SAS)

AF:

0.00

AC:

AN:

72896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49642

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1067400

Other (OTH)

AF:

0.0000177

AC:

AN:

56538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.041

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.59

M_CAP

Benign

0.062

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.81

PhyloP100

3.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.50

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.47

Vest4

0.40

MutPred

0.67

Gain of disorder (P = 0.0434)

MVP

0.76

MPC

0.015

ClinPred

0.61

GERP RS

4.6

Varity_R

0.51

gMVP

0.68

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over