3-9829346-T-G

Variant names:

• chr3-9829346-T-G
• rs2290305
• NM_001387446.1:c.1634T>G

Variant summary

Our verdict is Benign. The variant received -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. 14/19 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
• Publications: 29 publications found

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:38830): (ARPC4-TTLL3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ARPC4 (actin related protein 2/3 complex, subunit 4) and TTLL3 (tubulin tyrosine ligase-like family, member 3) genes. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387446.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL3	NM_001387446.1	MANE Select	c.1634T>G	p.Met545Arg	missense	Exon 11 of 14	NP_001374375.1
	TTLL3	NM_001025930.5		c.1934T>G	p.Met645Arg	missense	Exon 10 of 13	NP_001021100.3
	TTLL3	NM_001366051.2		c.1505T>G	p.Met502Arg	missense	Exon 10 of 13	NP_001352980.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL3	ENST00000685419.1	MANE Select	c.1634T>G	p.Met545Arg	missense	Exon 11 of 14	ENSP00000510679.1
	ARPC4-TTLL3	ENST00000397256.5	TSL:5	c.1688T>G	p.Met563Arg	missense	Exon 11 of 12	ENSP00000380427.1
	TTLL3	ENST00000310252.11	TSL:1	c.1370T>G	p.Met457Arg	missense	Exon 8 of 9	ENSP00000312148.7

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

GnomAD2 exomes AF: 0.591 AC: 146599 AN: 248048 AF XY: 0.600

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 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

African (AFR) AF: 0.592 AC: 19782 AN: 33440

American (AMR) AF: 0.390 AC: 17369 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 18738 AN: 26028

East Asian (EAS) AF: 0.201 AC: 7949 AN: 39612

South Asian (SAS) AF: 0.474 AC: 40738 AN: 86030

European-Finnish (FIN) AF: 0.771 AC: 40875 AN: 53046

Middle Eastern (MID) AF: 0.590 AC: 3350 AN: 5678

European-Non Finnish (NFE) AF: 0.701 AC: 777954 AN: 1109804

Other (OTH) AF: 0.642 AC: 38625 AN: 60194

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

African (AFR) AF: 0.596 AC: 24707 AN: 41482

American (AMR) AF: 0.531 AC: 8116 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 2497 AN: 3472

East Asian (EAS) AF: 0.191 AC: 987 AN: 5176

South Asian (SAS) AF: 0.445 AC: 2140 AN: 4814

European-Finnish (FIN) AF: 0.764 AC: 8097 AN: 10592

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47932 AN: 67980

Other (OTH) AF: 0.650 AC: 1374 AN: 2114

Alfa AF: 0.670 Hom.: 138962

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.018
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
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.99	T
PhyloP100		2.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	3.7	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.22
MPC		0.13
ClinPred		0.0025	T
GERP RS		4.1
PromoterAI		-0.077	Neutral
gMVP		0.70
Mutation Taster		=95/5	polymorphism (auto)

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