Genetic Variant ARPC4-TTLL3:c.331-2698G>T (chr3-9810245-G-T) – 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.239G>T(p.Gly80Val) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G80S) has been classified 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: -0.479

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=0.077828586).

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.239G>T	p.Gly80Val	missense	Exon 1 of 13	NP_001021100.3	J3KQB2
TTLL3	NM_001387448.1	c.-42+323G>T		intron	N/A	NP_001374377.1
ARPC4-TTLL3	NM_001198793.1	c.331-2698G>T		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.331-2698G>T	intron	N/A	ENSP00000380427.1
TTLL3	ENST00000427220.5	TSL:1	n.-417G>T	non_coding_transcript_exon	Exon 1 of 11	ENSP00000395912.1	F8WD18
TTLL3	ENST00000427220.5	TSL:1	n.-417G>T	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:

1356250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

668838

African (AFR)

AF:

0.00

AC:

AN:

27996

American (AMR)

AF:

0.00

AC:

AN:

32700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24064

East Asian (EAS)

AF:

0.00

AC:

AN:

32132

South Asian (SAS)

AF:

0.00

AC:

AN:

76466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4140

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068938

Other (OTH)

AF:

0.00

AC:

AN:

56578

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

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.9

(source)

DANN

Benign

0.81

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.39

M_CAP

Benign

0.010

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.94

PhyloP100

-0.48

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.0

REVEL

Benign

0.036

Sift

Benign

0.13

Sift4G

Benign

0.30

Vest4

0.056

MutPred

0.22

Gain of MoRF binding (P = 0.1136)

MVP

0.19

MPC

0.11

ClinPred

0.081

GERP RS

0.79

PromoterAI

0.61

Over-expression

(source)

gMVP

0.056

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