Genetic Variant TSSC4:p.Met116Ile (chr11-2402981-G-T) – 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.348G>T(p.Met116Ile) 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 1,457,088 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

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: -0.0410

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=0.03991759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSSC4	NM_005706.4 link	c.348G>T	p.Met116Ile	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.348G>T	p.Met116Ile	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:

1457088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33422

American (AMR)

AF:

0.00

AC:

AN:

44412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

85712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110318

Other (OTH)

AF:

0.00

AC:

AN:

60194

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

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.077

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.0067

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

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.34

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

M_CAP

Benign

0.0060

MetaRNN

Benign

0.040

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;L;.;.;.;.;L

PhyloP100

-0.041

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.040

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

REVEL

Benign

0.12

Sift

Benign

0.45

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

Sift4G

Benign

0.52

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

Polyphen

0.0

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

Vest4

0.059

MutPred

0.16

.;Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);

MVP

0.014

MPC

0.017

ClinPred

0.041

GERP RS

-2.1

Varity_R

0.028

gMVP

0.15

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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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