12-26995364-G-C

Position:

• chr12-26995364-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016551.3(TM7SF3):​c.563C>G​(p.Ser188Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TM7SF3 NM_016551.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31345785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TM7SF3	NM_016551.3	c.563C>G	p.Ser188Cys	missense_variant	5/12	ENST00000343028.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TM7SF3	ENST00000343028.9	c.563C>G	p.Ser188Cys	missense_variant	5/12	1	NM_016551.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 06, 2023

The c.563C>G (p.S188C) alteration is located in exon 5 (coding exon 5) of the TM7SF3 gene. This alteration results from a C to G substitution at nucleotide position 563, causing the serine (S) at amino acid position 188 to be replaced by a cysteine (C). 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	0.25
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.037	T;.;T;T
Eigen	Benign	0.048
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	0.87	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N;N;D
REVEL	Benign	0.18
Sift	Benign	0.045	D;D;D;D
Sift4G	Uncertain	0.012	D;.;.;.
Polyphen		0.98	D;.;.;.
Vest4		0.50
MutPred		0.43		Gain of catalytic residue at R189 (P = 0.0042);.;.;.;
MVP		0.33
MPC		0.53
ClinPred		0.80	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-27148297;