chr3-39109095-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001366900.1(TTC21A):c.38T>C(p.Ile13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000548 in 1,613,906 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

TTC21A
NM_001366900.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 0.684

Publications

4 publications found

Variant links:

Genes affected

TTC21A (HGNC:30761): (tetratricopeptide repeat domain 21A) Involved in flagellated sperm motility and spermatid development. Predicted to be located in cilium. Predicted to be part of intraciliary transport particle A. Implicated in spermatogenic failure 37. [provided by Alliance of Genome Resources, Apr 2022]

TTC21A Gene-Disease associations (from GenCC):

spermatogenic failure 37
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

TTC21A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009531677).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00198 (301/152280) while in subpopulation AFR AF = 0.00628 (261/41562). AF 95% confidence interval is 0.00565. There are 2 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366900.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC21A	NM_001366900.1	MANE Select	c.38T>C	p.Ile13Thr	missense	Exon 2 of 29	NP_001353829.1	A0A804HK20
TTC21A	NM_001366899.1		c.38T>C	p.Ile13Thr	missense	Exon 2 of 29	NP_001353828.1	A0A140VJY5
TTC21A	NM_145755.3		c.38T>C	p.Ile13Thr	missense	Exon 2 of 29	NP_665698.2	Q8NDW8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC21A	ENST00000683103.1	MANE Select	c.38T>C	p.Ile13Thr	missense	Exon 2 of 29	ENSP00000507739.1	A0A804HK20
TTC21A	ENST00000431162.6	TSL:1	c.38T>C	p.Ile13Thr	missense	Exon 2 of 29	ENSP00000398211.2	Q8NDW8-1
TTC21A	ENST00000479954.5	TSL:1	n.159T>C		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

300

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00630

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000677

AC:

169

AN:

249522

AF XY:

0.000606

show subpopulations

Gnomad AFR exome

AF:

0.00633

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000400

AC:

584

AN:

1461626

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

235

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00693

AC:

232

AN:

33480

American (AMR)

AF:

0.00105

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000228

AC:

253

AN:

1111820

Other (OTH)

AF:

0.000812

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

AF:

0.00198

AC:

301

AN:

152280

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00628

AC:

261

AN:

41562

American (AMR)

AF:

0.00105

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68010

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000844

Hom.:

Bravo

AF:

0.00217

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00358

AC:

ESP6500EA

AF:

0.000482

AC:

ExAC

AF:

0.000629

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

TTC21A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0061

Eigen

Benign

0.023

Eigen_PC

Benign

0.015

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.80

M_CAP

Benign

0.019

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.2

PhyloP100

0.68

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.3

REVEL

Benign

0.23

Sift

Benign

0.50

Sift4G

Benign

0.33

Polyphen

0.80

Vest4

0.38

MVP

0.72

MPC

0.19

ClinPred

0.013

GERP RS

4.3

Varity_R

0.087

gMVP

0.27

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over