20-31922980-C-G

Variant names:

• chr20-31922980-C-G
• rs749750682
• NM_001008409.5:c.591C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001008409.5(TTLL9):​c.591C>G​(p.Asp197Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,396 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TTLL9 NM_001008409.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 0 publications found

Genes affected

TTLL9 (HGNC:16118): (tubulin tyrosine ligase like 9) Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in microtubule cytoskeleton organization and protein polyglutamylation. Predicted to act upstream of or within flagellated sperm motility. Predicted to be located in ciliary basal body; cytoplasm; and microtubule. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

TTLL9 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040803254).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008409.5. 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
	TTLL9	NM_001008409.5	MANE Select	c.591C>G	p.Asp197Glu	missense	Exon 8 of 15	NP_001008409.1	Q3SXZ7-1
	TTLL9	NM_001367620.2		c.252C>G	p.Asp84Glu	missense	Exon 5 of 12	NP_001354549.1	A0A087X135
	TTLL9	NR_134519.4		n.998C>G		non_coding_transcript_exon	Exon 9 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL9	ENST00000535842.6	TSL:5 MANE Select	c.591C>G	p.Asp197Glu	missense	Exon 8 of 15	ENSP00000442515.1	Q3SXZ7-1
	TTLL9	ENST00000620043.4	TSL:1	c.252C>G	p.Asp84Glu	missense	Exon 5 of 12	ENSP00000483865.1	A0A087X135
	TTLL9	ENST00000310998.8	TSL:1	n.*286C>G		non_coding_transcript_exon	Exon 8 of 15	ENSP00000308980.5	A0A0A0MR21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461396 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727040

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111650

Other (OTH) AF: 0.0000166 AC: 1 AN: 60362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0104647), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.036
DANN	Benign	0.71
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.36	N
PhyloP100		-1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.044
Sift	Benign	0.64	T
Sift4G	Benign	0.74	T
Polyphen		0.0030	B
Vest4		0.099
MutPred		0.30		Loss of stability (P = 0.1522)
MVP		0.014
MPC		0.11
ClinPred		0.090	T
GERP RS		-4.0
Varity_R		0.033
gMVP		0.16
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs749750682; hg19: chr20-30510783;