Genetic Variant NM_001387446.1:c.-171C>T (chr3-9810265-C-T) – 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_001387446.1(TTLL3):c.-171C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000398 in 1,507,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

TTLL3
NM_001387446.1 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.116

Publications

0 publications found

Variant links:

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]

TTLL3 links:

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:

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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=0.053043783).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTLL3	NM_001387446.1	MANE Select	c.-171C>T		5_prime_UTR	Exon 1 of 14	NP_001374375.1	A0A8I5KXU2
TTLL3	NM_001025930.5		c.259C>T	p.Pro87Ser	missense	Exon 1 of 13	NP_001021100.3	J3KQB2
TTLL3	NM_001366051.2		c.-171C>T		5_prime_UTR	Exon 1 of 13	NP_001352980.1	Q9Y4R7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TTLL3	ENST00000685419.1	MANE Select	c.-171C>T	5_prime_UTR	Exon 1 of 14	ENSP00000510679.1	A0A8I5KXU2
ARPC4-TTLL3	ENST00000397256.5	TSL:5	c.331-2678C>T	intron	N/A	ENSP00000380427.1
TTLL3	ENST00000427220.5	TSL:1	n.-397C>T	non_coding_transcript_exon	Exon 1 of 11	ENSP00000395912.1	F8WD18

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000997

AC:

AN:

100288

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000166

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:

1355236

Hom.:

Cov.:

AF XY:

0.00000449

AC XY:

AN XY:

668468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27942

American (AMR)

AF:

0.00

AC:

AN:

32154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23988

East Asian (EAS)

AF:

0.0000621

AC:

AN:

32192

South Asian (SAS)

AF:

0.00

AC:

AN:

76404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4046

European-Non Finnish (NFE)

AF:

0.00000281

AC:

AN:

1068838

Other (OTH)

AF:

0.00

AC:

AN:

56518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

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

0.082

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.1

(source)

DANN

Benign

0.93

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.38

M_CAP

Benign

0.035

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.91

PhyloP100

-0.12

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.4

REVEL

Benign

0.032

Sift

Benign

0.46

Sift4G

Benign

0.49

Vest4

0.046

MutPred

0.15

Loss of glycosylation at P89 (P = 0.0196)

MVP

0.15

MPC

0.093

ClinPred

0.042

GERP RS

2.4

PromoterAI

0.076

Neutral

(source)

gMVP

0.053

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over