chr12-26974066-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016551.3(TM7SF3):ā€‹c.1612A>Gā€‹(p.Ile538Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000010 ( 0 hom. )

Consequence

TM7SF3
NM_016551.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.374
Variant links:
Genes affected
TM7SF3 (HGNC:23049): (transmembrane 7 superfamily member 3) Involved in cellular response to unfolded protein; negative regulation of programmed cell death; and positive regulation of insulin secretion. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.046702594).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TM7SF3NM_016551.3 linkuse as main transcriptc.1612A>G p.Ile538Val missense_variant 12/12 ENST00000343028.9
TM7SF3XM_017019463.3 linkuse as main transcriptc.1702A>G p.Ile568Val missense_variant 12/12
TM7SF3XM_047428990.1 linkuse as main transcriptc.1549A>G p.Ile517Val missense_variant 11/11
TM7SF3XM_005253391.5 linkuse as main transcriptc.1459A>G p.Ile487Val missense_variant 11/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TM7SF3ENST00000343028.9 linkuse as main transcriptc.1612A>G p.Ile538Val missense_variant 12/121 NM_016551.3 P1
ENST00000500632.1 linkuse as main transcriptn.960+1521T>C intron_variant, non_coding_transcript_variant 5
TM7SF3ENST00000544179.1 linkuse as main transcript downstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152166
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251398
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135874
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461888
Hom.:
0
Cov.:
30
AF XY:
0.00000688
AC XY:
5
AN XY:
727246
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:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000113

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 GeneticsFeb 14, 2023The c.1612A>G (p.I538V) alteration is located in exon 12 (coding exon 12) of the TM7SF3 gene. This alteration results from a A to G substitution at nucleotide position 1612, causing the isoleucine (I) at amino acid position 538 to be replaced by a valine (V). 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
0.083
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
12
DANN
Benign
0.74
DEOGEN2
Benign
0.0033
T
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.52
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.68
T
M_CAP
Benign
0.0035
T
MetaRNN
Benign
0.047
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
0.65
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
0.070
N
REVEL
Benign
0.033
Sift
Benign
0.61
T
Sift4G
Benign
0.67
T
Polyphen
0.0010
B
Vest4
0.062
MVP
0.11
MPC
0.12
ClinPred
0.037
T
GERP RS
0.19
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.016
gMVP
0.45

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1392467294; hg19: chr12-27126999; API