Variant 19-19268740-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001001524.3(TM6SF2):c.499G>A(p.Glu167Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0709 in 1,603,508 control chromosomes in the GnomAD database, including 4,135 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.059 ( 292 hom., cov: 32)

Exomes 𝑓: 0.072 ( 3843 hom. )

Consequence

TM6SF2
NM_001001524.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.46

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001992762).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0894 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TM6SF2	NM_001001524.3 linkuse as main transcript	c.499G>A	p.Glu167Lys	missense_variant	6/10	ENST00000389363.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TM6SF2	ENST00000389363.5 linkuse as main transcript	c.499G>A	p.Glu167Lys	missense_variant	6/10	1	NM_001001524.3	P1	Q9BZW4-1
TM6SF2	ENST00000586107.1 linkuse as main transcript	n.473G>A		non_coding_transcript_exon_variant	4/4	3
TM6SF2	ENST00000431465.2 linkuse as main transcript	n.1006-653G>A		intron_variant, non_coding_transcript_variant		2
TM6SF2	ENST00000591001.5 linkuse as main transcript	n.944-653G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0592

AC:

8996

AN:

152040

Hom.:

287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0338

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.0548

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.0747

Gnomad SAS

AF:

0.0969

Gnomad FIN

AF:

0.0585

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0723

Gnomad OTH

AF:

0.0489

GnomAD3 exomes

AF:

0.0654

AC:

15547

AN:

237850

Hom.:

580

AF XY:

0.0681

AC XY:

8833

AN XY:

129766

show subpopulations

Gnomad AFR exome

AF:

0.0318

Gnomad AMR exome

AF:

0.0372

Gnomad ASJ exome

AF:

0.0477

Gnomad EAS exome

AF:

0.0697

Gnomad SAS exome

AF:

0.0896

Gnomad FIN exome

AF:

0.0567

Gnomad NFE exome

AF:

0.0745

Gnomad OTH exome

AF:

0.0606

GnomAD4 exome

AF:

0.0721

AC:

104642

AN:

1451350

Hom.:

3843

Cov.:

AF XY:

0.0724

AC XY:

52298

AN XY:

722112

show subpopulations

Gnomad4 AFR exome

AF:

0.0311

Gnomad4 AMR exome

AF:

0.0378

Gnomad4 ASJ exome

AF:

0.0499

Gnomad4 EAS exome

AF:

0.0768

Gnomad4 SAS exome

AF:

0.0903

Gnomad4 FIN exome

AF:

0.0617

Gnomad4 NFE exome

AF:

0.0745

Gnomad4 OTH exome

AF:

0.0664

GnomAD4 genome

AF:

0.0593

AC:

9018

AN:

152158

Hom.:

292

Cov.:

AF XY:

0.0597

AC XY:

4445

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0339

Gnomad4 AMR

AF:

0.0547

Gnomad4 ASJ

AF:

0.0432

Gnomad4 EAS

AF:

0.0745

Gnomad4 SAS

AF:

0.0966

Gnomad4 FIN

AF:

0.0585

Gnomad4 NFE

AF:

0.0723

Gnomad4 OTH

AF:

0.0569

Alfa

AF:

0.0683

Hom.:

632

Bravo

AF:

0.0574

TwinsUK

AF:

0.0787

AC:

292

ALSPAC

AF:

0.0680

AC:

262

ESP6500AA

AF:

0.0308

AC:

126

ESP6500EA

AF:

0.0714

AC:

599

ExAC

AF:

0.0712

AC:

8619

Asia WGS

AF:

0.120

AC:

416

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0021

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.0041

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.2

REVEL

Benign

0.075

Sift

Benign

0.30

Sift4G

Benign

0.30

Polyphen

1.0

Vest4

0.18

MPC

0.39

ClinPred

0.018

GERP RS

5.0

Varity_R

0.13

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over