Variant 22-46283974-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000381031.8(TTC38):c.737A>G(p.Asp246Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000197 in 1,521,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

TTC38
ENST00000381031.8 missense, splice_region

Scores

Splicing: ADA: 0.00009090

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.695

Variant links:

Genes affected

TTC38 (HGNC:26082): (tetratricopeptide repeat domain 38) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

TTC38 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042734742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TTC38	NM_017931.4 linkuse as main transcript	c.737A>G	p.Asp246Gly	missense_variant, splice_region_variant	8/14	ENST00000381031.8	NP_060401.3
TTC38	XM_047441438.1 linkuse as main transcript	c.542A>G	p.Asp181Gly	missense_variant, splice_region_variant	8/14		XP_047297394.1
TTC38	XM_047441439.1 linkuse as main transcript	c.737A>G	p.Asp246Gly	missense_variant, splice_region_variant	8/10		XP_047297395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC38	ENST00000381031.8 linkuse as main transcript	c.737A>G	p.Asp246Gly	missense_variant, splice_region_variant	8/14	1	NM_017931.4	ENSP00000370419	P1
TTC38	ENST00000422713.1 linkuse as main transcript	c.*141A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	7/7	5		ENSP00000406604

Frequencies

GnomAD3 genomes

AF:

0.00000697

AC:

AN:

143392

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000421

AC:

AN:

237426

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129074

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000145

AC:

AN:

1378090

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686334

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000239

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.44e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000697

AC:

AN:

143392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69150

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000150

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2021

The c.737A>G (p.D246G) alteration is located in exon 8 (coding exon 8) of the TTC38 gene. This alteration results from a A to G substitution at nucleotide position 737, causing the aspartic acid (D) at amino acid position 246 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.54

DEOGEN2

Benign

0.035

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.77

M_CAP

Benign

0.015

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.58

D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

REVEL

Benign

0.046

Sift

Benign

0.35

Sift4G

Benign

0.42

Polyphen

0.0010

Vest4

0.15

MutPred

0.27

Gain of methylation at K245 (P = 0.0735);

MVP

0.076

MPC

0.27

ClinPred

0.044

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000091

dbscSNV1_RF

Benign

0.018

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over