Genetic Variant NM_005706.4:c.341C>A (chr11-2402974-C-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.341C>A(p.Thr114Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T114I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TSSC4
NM_005706.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.32

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=0.042291284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSSC4	NM_005706.4 link	c.341C>A	p.Thr114Asn	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.341C>A	p.Thr114Asn	missense_variant	Exon 3 of 3	1	NM_005706.4	ENSP00000331087.6		Q9Y5U2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457670

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

85766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110638

Other (OTH)

AF:

0.00

AC:

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.3

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.0062

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.35

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.042

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

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

PhyloP100

1.3

PrimateAI

Benign

0.47

PROVEAN

Benign

0.18

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

REVEL

Benign

0.023

Sift

Benign

0.49

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

Sift4G

Benign

0.51

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

Polyphen

0.078

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

Vest4

0.038

MutPred

0.18

.;Gain of relative solvent accessibility (P = 0.0082);.;Gain of relative solvent accessibility (P = 0.0082);.;Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);

MVP

0.072

MPC

0.034

ClinPred

0.059

GERP RS

0.81

Varity_R

0.059

gMVP

0.22

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over