11-2402900-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005706.4(TSSC4):c.267C>G(p.Phe89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSSC4 NM_005706.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSSC4	NM_005706.4	c.267C>G	p.Phe89Leu	missense_variant	3/3	ENST00000333256.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSSC4	ENST00000333256.11	c.267C>G	p.Phe89Leu	missense_variant	3/3	1	NM_005706.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Jan 12, 2024

The c.267C>G (p.F89L) alteration is located in exon 2 (coding exon 1) of the TSSC4 gene. This alteration results from a C to G substitution at nucleotide position 267, causing the phenylalanine (F) at amino acid position 89 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T;.;D;D;D;D;D;D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.97	D;D;.;.;.;.;.;.;D
Vest4		0.88
MutPred		0.51		.;Gain of MoRF binding (P = 0.1254);.;Gain of MoRF binding (P = 0.1254);Gain of MoRF binding (P = 0.1254);Gain of MoRF binding (P = 0.1254);.;Gain of MoRF binding (P = 0.1254);Gain of MoRF binding (P = 0.1254);
MVP		0.53
MPC		0.13
ClinPred		0.99	D
GERP RS		1.5
Varity_R		0.98
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs1369059256; hg19: chr11-2424130;