Genetic Variant TTC21A:p.Glu168Lys (chr3-39112524-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001366900.1(TTC21A):c.502G>A(p.Glu168Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,614,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TTC21A
NM_001366900.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.16

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020091534).

BP6

Variant 3-39112524-G-A is Benign according to our data. Variant chr3-39112524-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3184157.Status of the report is criteria_provided_single_submitter, 1 stars.

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.502G>A	p.Glu168Lys	missense	Exon 5 of 29	NP_001353829.1	A0A804HK20
TTC21A	NM_001366899.1		c.502G>A	p.Glu168Lys	missense	Exon 5 of 29	NP_001353828.1	A0A140VJY5
TTC21A	NM_145755.3		c.502G>A	p.Glu168Lys	missense	Exon 5 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.502G>A	p.Glu168Lys	missense	Exon 5 of 29	ENSP00000507739.1	A0A804HK20
TTC21A	ENST00000431162.6	TSL:1	c.502G>A	p.Glu168Lys	missense	Exon 5 of 29	ENSP00000398211.2	Q8NDW8-1
TTC21A	ENST00000479954.5	TSL:1	n.623G>A		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.0000401

AC:

AN:

249456

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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

AF:

0.0000788

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.0000579

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.0010

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.75

M_CAP

Benign

0.0090

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.4

PhyloP100

5.2

PrimateAI

Benign

0.37

PROVEAN

Benign

2.2

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.17

MutPred

0.41

Gain of glycosylation at Y169 (P = 0.0166)

MVP

0.32

MPC

0.14

ClinPred

0.014

GERP RS

4.6

Varity_R

0.050

gMVP

0.10

Mutation Taster

=96/4

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