Genetic Variant TSSC4:p.Ser117Asn (chr11-2402983-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.350G>A(p.Ser117Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,457,218 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: 0.000021 ( 0 hom. )

Consequence

TSSC4
NM_005706.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.689

Publications

0 publications found

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=0.06009522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSSC4	NM_005706.4 link	c.350G>A	p.Ser117Asn	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.350G>A	p.Ser117Asn	missense_variant	Exon 3 of 3	1	NM_005706.4	ENSP00000331087.6		Q9Y5U2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

241008

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1457218

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

724502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

85706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1110392

Other (OTH)

AF:

0.00

AC:

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.350G>A (p.S117N) 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 350, causing the serine (S) at amino acid position 117 to be replaced by an asparagine (N). 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

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.3

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0054

.;T;T;T;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.44

T;.;T;T;T;T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.060

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;M;.;.;.;.;M

PhyloP100

0.69

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.26

N;N;N;N;N;N;N

REVEL

Benign

0.012

Sift

Benign

0.53

T;T;T;T;T;T;T

Sift4G

Benign

0.50

T;T;T;T;T;T;T

Polyphen

0.0

B;B;.;.;.;.;B

Vest4

0.069

MVP

0.030

MPC

0.016

ClinPred

0.029

GERP RS

-1.2

Varity_R

0.032

gMVP

0.17

Mutation Taster

=96/4

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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11-2402983-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over