chr12-26974152-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_016551.3(TM7SF3):​c.1526G>A​(p.Arg509Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

TM7SF3
NM_016551.3 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.207
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.026120752).
BP6
Variant 12-26974152-C-T is Benign according to our data. Variant chr12-26974152-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3326477.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TM7SF3NM_016551.3 linkuse as main transcriptc.1526G>A p.Arg509Gln missense_variant 12/12 ENST00000343028.9 NP_057635.1
TM7SF3XM_017019463.3 linkuse as main transcriptc.1616G>A p.Arg539Gln missense_variant 12/12 XP_016874952.1
TM7SF3XM_047428990.1 linkuse as main transcriptc.1463G>A p.Arg488Gln missense_variant 11/11 XP_047284946.1
TM7SF3XM_005253391.5 linkuse as main transcriptc.1373G>A p.Arg458Gln missense_variant 11/11 XP_005253448.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TM7SF3ENST00000343028.9 linkuse as main transcriptc.1526G>A p.Arg509Gln missense_variant 12/121 NM_016551.3 ENSP00000342322 P1
ENST00000500632.1 linkuse as main transcriptn.960+1607C>T intron_variant, non_coding_transcript_variant 5
TM7SF3ENST00000544179.1 linkuse as main transcriptn.356G>A non_coding_transcript_exon_variant 2/22
TM7SF3ENST00000545344.5 linkuse as main transcript downstream_gene_variant 3 ENSP00000445756

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251350
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135844
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461870
Hom.:
0
Cov.:
30
AF XY:
0.0000206
AC XY:
15
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000705
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000104
Hom.:
0
ExAC
AF:
0.0000494
AC:
6
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
4.8
DANN
Uncertain
0.98
DEOGEN2
Benign
0.026
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.049
N
LIST_S2
Benign
0.83
T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.026
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.050
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.048
Sift
Benign
0.20
T
Sift4G
Benign
0.22
T
Polyphen
0.17
B
Vest4
0.054
MutPred
0.34
Gain of catalytic residue at P513 (P = 2e-04);
MVP
0.20
MPC
0.17
ClinPred
0.045
T
GERP RS
-3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.034
gMVP
0.56

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: rs762705907; hg19: chr12-27127085; COSMIC: COSV100544902; COSMIC: COSV100544902; API