19-19268740-C-T

Variant names:

• chr19-19268740-C-T
• rs58542926
• NM_001001524.3:c.499G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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.

• Frequency:
  • Genomes: 𝑓 0.059 (292 hom., cov: 32)
  • Exomes 𝑓: 0.072 (3843 hom.)
• Consequence: TM6SF2 NM_001001524.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.46
• Publications: 970 publications found

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]

ENSG00000267629 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TM6SF2	NM_001001524.3	c.499G>A	p.Glu167Lys	missense_variant	Exon 6 of 10	ENST00000389363.5	NP_001001524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM6SF2	ENST00000389363.5	c.499G>A	p.Glu167Lys	missense_variant	Exon 6 of 10	1	NM_001001524.3	ENSP00000374014.2

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 8996 AN: 152040 Hom.: 287 Cov.: 32

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

GnomAD2 exomes AF: 0.0654 AC: 15547 AN: 237850 AF XY: 0.0681

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 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.: 31 AF XY: 0.0724 AC XY: 52298 AN XY: 722112

African (AFR) AF: 0.0311 AC: 1013 AN: 32544

American (AMR) AF: 0.0378 AC: 1602 AN: 42402

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 1290 AN: 25842

East Asian (EAS) AF: 0.0768 AC: 2978 AN: 38756

South Asian (SAS) AF: 0.0903 AC: 7640 AN: 84580

European-Finnish (FIN) AF: 0.0617 AC: 3289 AN: 53270

Middle Eastern (MID) AF: 0.0439 AC: 252 AN: 5742

European-Non Finnish (NFE) AF: 0.0745 AC: 82596 AN: 1108240

Other (OTH) AF: 0.0664 AC: 3982 AN: 59974

GnomAD4 genome AF: 0.0593 AC: 9018 AN: 152158 Hom.: 292 Cov.: 32 AF XY: 0.0597 AC XY: 4445 AN XY: 74394

African (AFR) AF: 0.0339 AC: 1408 AN: 41508

American (AMR) AF: 0.0547 AC: 836 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3472

East Asian (EAS) AF: 0.0745 AC: 385 AN: 5166

South Asian (SAS) AF: 0.0966 AC: 466 AN: 4824

European-Finnish (FIN) AF: 0.0585 AC: 619 AN: 10588

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0723 AC: 4914 AN: 67998

Other (OTH) AF: 0.0569 AC: 120 AN: 2110

Alfa AF: 0.0685 Hom.: 1334

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	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0021	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.075
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.18
MPC		0.39
ClinPred		0.018	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.42
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs58542926; hg19: chr19-19379549; COSMIC: COSV66985100; COSMIC: COSV66985100;