Variant 19-19266513-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001001524.3(TM6SF2):c.901G>T(p.Val301Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

TM6SF2
NM_001001524.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.960

Variant links:

Genes affected

TM6SF2 (HGNC:11861): (transmembrane 6 superfamily member 2) Enables identical protein binding activity. Involved in regulation of lipid metabolic process. Located in endoplasmic reticulum membrane and endoplasmic reticulum-Golgi intermediate compartment membrane. [provided by Alliance of Genome Resources, Apr 2022]

TM6SF2 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=0.03648871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM6SF2	NM_001001524.3 linkuse as main transcript	c.901G>T	p.Val301Leu	missense_variant	9/10	ENST00000389363.5	NP_001001524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM6SF2	ENST00000389363.5 linkuse as main transcript	c.901G>T	p.Val301Leu	missense_variant	9/10	1	NM_001001524.3	ENSP00000374014	P1	Q9BZW4-1
TM6SF2	ENST00000431465.2 linkuse as main transcript	n.1297G>T		non_coding_transcript_exon_variant	6/7	2
TM6SF2	ENST00000590431.6 linkuse as main transcript	n.204G>T		non_coding_transcript_exon_variant	1/2	3
TM6SF2	ENST00000591001.5 linkuse as main transcript	n.1235G>T		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

249436

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135308

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.000112

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000269

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000866

Hom.:

Bravo

AF:

0.000310

ESP6500AA

AF:

0.000935

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000908

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Jul 06, 2021

The c.901G>T (p.V301L) alteration is located in exon 9 (coding exon 9) of the TM6SF2 gene. This alteration results from a G to T substitution at nucleotide position 901, causing the valine (V) at amino acid position 301 to be replaced by a leucine (L). 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

0.17

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0048

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.071

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.81

M_CAP

Benign

0.0087

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.59

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.76

REVEL

Benign

0.033

Sift

Benign

0.18

Sift4G

Benign

0.31

Polyphen

0.0030

Vest4

0.34

MutPred

0.26

Loss of catalytic residue at V301 (P = 0.1708);

MVP

0.20

MPC

0.28

ClinPred

0.021

GERP RS

4.3

Varity_R

0.068

gMVP

0.63

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