rs190808723

Variant names:

• chr3-39109123-C-T
• rs190808723
• NM_001366900.1:c.66C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001366900.1(TTC21A):​c.66C>T​(p.His22His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,614,142 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: TTC21A NM_001366900.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.382
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-39109123-C-T is Benign according to our data. Variant chr3-39109123-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3388204.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.382 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000958 (146/152338) while in subpopulation AMR AF = 0.00242 (37/15306). AF 95% confidence interval is 0.0018. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21A	NM_001366900.1	MANE Select	c.66C>T	p.His22His	synonymous	Exon 2 of 29	NP_001353829.1	A0A804HK20
	TTC21A	NM_001366899.1		c.66C>T	p.His22His	synonymous	Exon 2 of 29	NP_001353828.1	A0A140VJY5
	TTC21A	NM_145755.3		c.66C>T	p.His22His	synonymous	Exon 2 of 29	NP_665698.2	Q8NDW8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21A	ENST00000683103.1	MANE Select	c.66C>T	p.His22His	synonymous	Exon 2 of 29	ENSP00000507739.1	A0A804HK20
	TTC21A	ENST00000431162.6	TSL:1	c.66C>T	p.His22His	synonymous	Exon 2 of 29	ENSP00000398211.2	Q8NDW8-1
	TTC21A	ENST00000479954.5	TSL:1	n.187C>T		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

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: 0.00143

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000886 AC: 221 AN: 249566 AF XY: 0.000901

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00101 AC: 1476 AN: 1461804 Hom.: 4 Cov.: 31 AF XY: 0.000985 AC XY: 716 AN XY: 727214

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00233 AC: 104 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53408

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00116 AC: 1294 AN: 1111938

Other (OTH) AF: 0.00106 AC: 64 AN: 60394

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74490

African (AFR) AF: 0.000168 AC: 7 AN: 41580

American (AMR) AF: 0.00242 AC: 37 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00119

EpiCase AF: 0.00153

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.4
DANN	Benign	0.56
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs190808723; hg19: chr3-39150614; COSMIC: COSV57189320; COSMIC: COSV57189320;