dbSNP rs764005263: TSSC4:p.Gly306Ser (chr11-2403549-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005706.4(TSSC4):c.916G>A(p.Gly306Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000237 in 1,433,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

TSSC4
NM_005706.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.616

Variant links:

Genes affected

TSSC4 (HGNC:12386): (tumor suppressing subtransferable candidate 4) This gene is one of several tumor-suppressing subtransferable fragments located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. This gene is located among several imprinted genes; however, this gene, as well as the pan-hematopoietic expression gene (PHEMX), escapes imprinting. This gene may play a role in malignancies and disease that involve this region. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

TSSC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040939778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSSC4	NM_005706.4 link	c.916G>A	p.Gly306Ser	missense_variant	Exon 3 of 3	ENST00000333256.11	NP_005697.2	Q9Y5U2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSSC4	ENST00000333256.11 link	c.916G>A	p.Gly306Ser	missense_variant	Exon 3 of 3	1	NM_005706.4	ENSP00000331087.6		Q9Y5U2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

221180

AF XY:

0.0000167

show subpopulations

Gnomad AFR exome

AF:

0.0000640

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000198

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1433588

Hom.:

Cov.:

AF XY:

0.0000239

AC XY:

AN XY:

711630

show subpopulations

African (AFR)

AF:

0.0000309

AC:

AN:

32406

American (AMR)

AF:

0.00

AC:

AN:

39636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24118

East Asian (EAS)

AF:

0.00

AC:

AN:

39330

South Asian (SAS)

AF:

0.00

AC:

AN:

82142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.0000291

AC:

AN:

1099378

Other (OTH)

AF:

0.0000169

AC:

AN:

59158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 01, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.916G>A (p.G306S) alteration is located in exon 2 (coding exon 1) of the TSSC4 gene. This alteration results from a G to A substitution at nucleotide position 916, causing the glycine (G) at amino acid position 306 to be replaced by a serine (S). 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

0.072

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0093

.;T;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.62

T;.;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.041

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

.;L;L

PhyloP100

0.62

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.017

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.028

B;B;B

Vest4

0.10

MutPred

0.30

.;Gain of phosphorylation at G306 (P = 0.0319);Gain of phosphorylation at G306 (P = 0.0319);

MVP

0.030

MPC

0.021

ClinPred

0.028

GERP RS

0.88

Varity_R

0.046

gMVP

0.034

Mutation Taster

=93/7

polymorphism

(source)

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

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rs764005263

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over