3-9829346-T-G

Position:

• chr3-9829346-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001387446.1(TTLL3):​c.1634T>G​(p.Met545Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 1,610,512 control chromosomes in the GnomAD database, including 361,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.64 (31808 hom., cov: 32)
  • Exomes 𝑓: 0.66 (329314 hom.)
• Consequence: TTLL3 NM_001387446.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35

Genes affected

TTLL3 (HGNC:24483): (tubulin tyrosine ligase like 3) Enables protein-glycine ligase activity. Predicted to be involved in axoneme assembly and flagellated sperm motility. Predicted to be located in axoneme; microtubule cytoskeleton; and sperm flagellum. [provided by Alliance of Genome Resources, Apr 2022]

ARPC4-TTLL3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8662956E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL3	NM_001387446.1	c.1634T>G	p.Met545Arg	missense_variant	11/14	ENST00000685419.1	NP_001374375.1
ARPC4-TTLL3	NM_001198793.1	c.1688T>G	p.Met563Arg	missense_variant	11/12		NP_001185722.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTLL3	ENST00000685419.1	c.1634T>G	p.Met545Arg	missense_variant	11/14		NM_001387446.1	ENSP00000510679	A2

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96716 AN: 151998 Hom.: 31792 Cov.: 32

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.764

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.647

GnomAD3 exomes AF: 0.591 AC: 146599 AN: 248048 Hom.: 47397 AF XY: 0.600 AC XY: 80613 AN XY: 134362

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.372

Gnomad ASJ exome AF: 0.714

Gnomad EAS exome AF: 0.188

Gnomad SAS exome AF: 0.474

Gnomad FIN exome AF: 0.775

Gnomad NFE exome AF: 0.708

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.662 AC: 965380 AN: 1458394 Hom.: 329314 Cov.: 101 AF XY: 0.658 AC XY: 477407 AN XY: 724998

Gnomad4 AFR exome AF: 0.592

Gnomad4 AMR exome AF: 0.390

Gnomad4 ASJ exome AF: 0.720

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.474

Gnomad4 FIN exome AF: 0.771

Gnomad4 NFE exome AF: 0.701

Gnomad4 OTH exome AF: 0.642

GnomAD4 genome AF: 0.636 AC: 96767 AN: 152118 Hom.: 31808 Cov.: 32 AF XY: 0.633 AC XY: 47066 AN XY: 74376

Gnomad4 AFR AF: 0.596

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.719

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.764

Gnomad4 NFE AF: 0.705

Gnomad4 OTH AF: 0.650

Alfa AF: 0.675 Hom.: 72357

Bravo AF: 0.617

TwinsUK AF: 0.694 AC: 2574

ALSPAC AF: 0.698 AC: 2690

ESP6500AA AF: 0.585 AC: 2577

ESP6500EA AF: 0.696 AC: 5983

ExAC AF: 0.597 AC: 72398

EpiCase AF: 0.699

EpiControl AF: 0.698

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.62
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.39	T;T;T;.;T;T
MetaRNN	Benign	0.0000019	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	3.7	N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;B;B
Vest4		0.22
MPC		0.13
ClinPred		0.0025	T
GERP RS		4.1
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs2290305; hg19: chr3-9871030; COSMIC: COSV59613381; COSMIC: COSV59613381;