chr19-19267685-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The ENST00000389363.5(TM6SF2):c.740G>T(p.Cys247Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,892 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: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
TM6SF2
ENST00000389363.5 missense
ENST00000389363.5 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 5.09
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.814
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TM6SF2 | NM_001001524.3 | c.740G>T | p.Cys247Phe | missense_variant | 8/10 | ENST00000389363.5 | NP_001001524.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TM6SF2 | ENST00000389363.5 | c.740G>T | p.Cys247Phe | missense_variant | 8/10 | 1 | NM_001001524.3 | ENSP00000374014.2 | ||
TM6SF2 | ENST00000431465.2 | n.1136G>T | non_coding_transcript_exon_variant | 5/7 | 2 | |||||
ENSG00000267629 | ENST00000586064.3 | n.837G>T | non_coding_transcript_exon_variant | 6/12 | 2 | |||||
TM6SF2 | ENST00000591001.5 | n.1074G>T | non_coding_transcript_exon_variant | 5/7 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152096Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248776Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135016
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461678Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727132
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152214Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74406
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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 | Apr 19, 2024 | The c.740G>T (p.C247F) alteration is located in exon 8 (coding exon 8) of the TM6SF2 gene. This alteration results from a G to T substitution at nucleotide position 740, causing the cysteine (C) at amino acid position 247 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -20
Find out detailed SpliceAI scores and Pangolin per-transcript scores at