11-65113350-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003273.6(TM7SF2):​c.435C>A​(p.Ser145Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,936 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 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

TM7SF2
NM_003273.6 missense

Scores

12
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.06
Variant links:
Genes affected
TM7SF2 (HGNC:11863): (transmembrane 7 superfamily member 2) Enables delta14-sterol reductase activity. Involved in cholesterol biosynthetic process. Located in endoplasmic reticulum. Part of receptor complex. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TM7SF2NM_003273.6 linkuse as main transcriptc.435C>A p.Ser145Arg missense_variant 4/10 ENST00000279263.14 NP_003264.2
TM7SF2NM_001277233.2 linkuse as main transcriptc.435C>A p.Ser145Arg missense_variant 4/9 NP_001264162.1
TM7SF2NR_102367.2 linkuse as main transcriptn.524C>A non_coding_transcript_exon_variant 3/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TM7SF2ENST00000279263.14 linkuse as main transcriptc.435C>A p.Ser145Arg missense_variant 4/101 NM_003273.6 ENSP00000279263 P1O76062-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152194
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249442
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135338
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461742
Hom.:
0
Cov.:
33
AF XY:
0.00000825
AC XY:
6
AN XY:
727176
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152194
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

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 submitterclinical testingAmbry GeneticsMar 22, 2022The c.435C>A (p.S145R) alteration is located in exon 4 (coding exon 4) of the TM7SF2 gene. This alteration results from a C to A substitution at nucleotide position 435, causing the serine (S) at amino acid position 145 to be replaced by an arginine (R). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;D;D;.;.
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.84
T;T;T;T;T
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H;.;.;H;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-4.8
D;D;D;D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
D;.;.;D;.
Vest4
0.91
MutPred
0.89
Gain of methylation at S145 (P = 0.032);.;.;Gain of methylation at S145 (P = 0.032);Gain of methylation at S145 (P = 0.032);
MVP
0.98
MPC
1.1
ClinPred
1.0
D
GERP RS
3.9
Varity_R
0.98
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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.

Other links and lift over

dbSNP: rs1459365131; hg19: chr11-64880822; API