Genetic Variant ARPC4-TTLL3:c.331-2698G>A (chr3-9810245-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001025930.5(TTLL3):c.239G>A(p.Gly80Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000369 in 1,356,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G80V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

TTLL3
NM_001025930.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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: 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=0.059364974).

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>A	p.Gly80Asp	missense	Exon 1 of 13	NP_001021100.3	J3KQB2
TTLL3	NM_001387448.1	c.-42+323G>A		intron	N/A	NP_001374377.1
ARPC4-TTLL3	NM_001198793.1	c.331-2698G>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.331-2698G>A	intron	N/A	ENSP00000380427.1
TTLL3	ENST00000427220.5	TSL:1	n.-417G>A	non_coding_transcript_exon	Exon 1 of 11	ENSP00000395912.1	F8WD18
TTLL3	ENST00000427220.5	TSL:1	n.-417G>A	5_prime_UTR	Exon 1 of 11	ENSP00000395912.1	F8WD18

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000985

AC:

AN:

101550

AF XY:

0.0000176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000369

AC:

AN:

1356250

Hom.:

Cov.:

AF XY:

0.00000449

AC XY:

AN XY:

668838

show subpopulations

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:

0.0000654

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

5.6

(source)

DANN

Benign

0.75

Eigen

Benign

-0.91

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.36

M_CAP

Benign

0.014

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.91

PhyloP100

-0.48

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.66

REVEL

Benign

0.017

Sift

Benign

0.25

Sift4G

Benign

0.60

Vest4

0.047

MutPred

0.15

Loss of helix (P = 0.079)

MVP

0.099

MPC

0.12

ClinPred

0.054

GERP RS

0.79

PromoterAI

-0.020

Neutral

(source)

gMVP

0.059

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over