Genetic Variant ARPC4-TTLL3:c.331-2800G>A (chr3-9810143-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001025930.5(TTLL3):c.137G>A(p.Arg46His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTLL3
NM_001025930.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.423

Publications

0 publications found

Variant links:

Genes affected

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]

ARPC4-TTLL3 links:

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]

TTLL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08032879).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025930.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTLL3	NM_001025930.5	c.137G>A	p.Arg46His	missense	Exon 1 of 13	NP_001021100.3	J3KQB2
TTLL3	NM_001387448.1	c.-42+221G>A		intron	N/A	NP_001374377.1
ARPC4-TTLL3	NM_001198793.1	c.331-2800G>A		intron	N/A	NP_001185722.1	A0A0A6YYG9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARPC4-TTLL3	ENST00000397256.5	TSL:5	c.331-2800G>A	intron	N/A	ENSP00000380427.1
TTLL3	ENST00000427220.5	TSL:1	n.-519G>A	non_coding_transcript_exon	Exon 1 of 11	ENSP00000395912.1	F8WD18
TTLL3	ENST00000427220.5	TSL:1	n.-519G>A	5_prime_UTR	Exon 1 of 11	ENSP00000395912.1	F8WD18

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1322384

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

651310

African (AFR)

AF:

0.00

AC:

AN:

26718

American (AMR)

AF:

0.00

AC:

AN:

25714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23386

East Asian (EAS)

AF:

0.00

AC:

AN:

28704

South Asian (SAS)

AF:

0.00

AC:

AN:

73048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4406

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1052542

Other (OTH)

AF:

0.00

AC:

AN:

55006

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.9

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.55

M_CAP

Benign

0.031

MetaRNN

Benign

0.080

MetaSVM

Benign

-1.0

PhyloP100

-0.42

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.67

REVEL

Benign

0.020

Sift

Uncertain

0.011

Sift4G

Uncertain

0.021

Vest4

0.037

MutPred

0.17

Gain of glycosylation at S48 (P = 0.0118)

MVP

0.076

MPC

0.11

ClinPred

0.18

GERP RS

0.37

PromoterAI

0.13

Neutral

(source)

gMVP

0.14

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over