19-19273160-G-A

Position:

• chr19-19273160-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001001524.3(TM6SF2):​c.56C>T​(p.Pro19Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000122 in 1,310,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TM6SF2 NM_001001524.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM6SF2	NM_001001524.3	c.56C>T	p.Pro19Leu	missense_variant	1/10	ENST00000389363.5	NP_001001524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM6SF2	ENST00000389363.5	c.56C>T	p.Pro19Leu	missense_variant	1/10	1	NM_001001524.3	ENSP00000374014	P1
TM6SF2	ENST00000431465.2	n.106C>T		non_coding_transcript_exon_variant	1/7	2
TM6SF2	ENST00000586107.1	n.232C>T		non_coding_transcript_exon_variant	1/4	3
TM6SF2	ENST00000591001.5	n.97C>T		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000122 AC: 16 AN: 1310006 Hom.: 0 Cov.: 32 AF XY: 0.00000929 AC XY: 6 AN XY: 645574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2022

The c.56C>T (p.P19L) alteration is located in exon 1 (coding exon 1) of the TM6SF2 gene. This alteration results from a C to T substitution at nucleotide position 56, causing the proline (P) at amino acid position 19 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	0.23
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.89	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.68		Loss of sheet (P = 0.0084);
MVP		0.33
MPC		0.90
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.24
gMVP		0.68

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

Other links and lift over

dbSNP: rs576994101; hg19: chr19-19383969;