Variant 15-83112825-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_023003.5(TM6SF1):c.121C>G(p.Leu41Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000021 ( 0 hom. )

Consequence

TM6SF1
NM_023003.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.674

Variant links:

Genes affected

TM6SF1 (HGNC:11860): (transmembrane 6 superfamily member 1) Predicted to be integral component of membrane. Predicted to be active in lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

TM6SF1 links:

HDGFL3 (HGNC:24937): (HDGF like 3) Predicted to enable double-stranded DNA binding activity; microtubule binding activity; and transcription coregulator activity. Predicted to be involved in several processes, including microtubule polymerization; negative regulation of microtubule depolymerization; and neuron projection development. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

HDGFL3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08577871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM6SF1	NM_023003.5 linkuse as main transcript	c.121C>G	p.Leu41Val	missense_variant	2/10	ENST00000322019.14	NP_075379.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM6SF1	ENST00000322019.14 linkuse as main transcript	c.121C>G	p.Leu41Val	missense_variant	2/10	1	NM_023003.5	ENSP00000317000	P1	Q9BZW5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251468

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135910

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 SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

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

Sep 22, 2022

The c.121C>G (p.L41V) alteration is located in exon 2 (coding exon 2) of the TM6SF1 gene. This alteration results from a C to G substitution at nucleotide position 121, causing the leucine (L) at amino acid position 41 to be replaced by a valine (V). 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

0.058

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.020

T;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.086

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.1

L;.;L

MutationTaster

Benign

0.75

D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.91

N;N;N

REVEL

Benign

0.015

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.049

B;B;.

Vest4

0.14

MVP

0.18

MPC

0.21

ClinPred

0.15

GERP RS

3.9

Varity_R

0.081

gMVP

0.54

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

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