chr11-2403085-C-T

Variant names:

• chr11-2403085-C-T
• rs760640459
• NM_005706.4:c.452C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005706.4(TSSC4):​c.452C>T​(p.Pro151Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,611,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: TSSC4 NM_005706.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1394819).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005706.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSSC4	NM_005706.4	MANE Select	c.452C>T	p.Pro151Leu	missense	Exon 3 of 3	NP_005697.2
	TSSC4	NM_001297658.2		c.452C>T	p.Pro151Leu	missense	Exon 4 of 4	NP_001284587.1	Q9Y5U2-1
	TSSC4	NM_001297659.2		c.452C>T	p.Pro151Leu	missense	Exon 3 of 3	NP_001284588.1	Q9Y5U2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSSC4	ENST00000333256.11	TSL:1 MANE Select	c.452C>T	p.Pro151Leu	missense	Exon 3 of 3	ENSP00000331087.6	Q9Y5U2-1
	TSSC4	ENST00000451491.2	TSL:1	c.452C>T	p.Pro151Leu	missense	Exon 2 of 2	ENSP00000411224.2	Q9Y5U2-1
	TSSC4	ENST00000380996.9	TSL:1	c.260C>T	p.Pro87Leu	missense	Exon 4 of 4	ENSP00000370384.5	Q9Y5U2-2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000823 AC: 2 AN: 242960 AF XY: 0.00000752

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: 0.0000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1459228 Hom.: 0 Cov.: 30 AF XY: 0.0000262 AC XY: 19 AN XY: 725862

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.0000225 AC: 1 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111502

Other (OTH) AF: 0.0000664 AC: 4 AN: 60278

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.12
Sift	Benign	0.045	D
Sift4G	Uncertain	0.020	D
Polyphen		0.57	P
Vest4		0.10
MutPred		0.26		Loss of disorder (P = 0.031)
MVP		0.20
MPC		0.077
ClinPred		0.36	T
GERP RS		1.6
Varity_R		0.099
gMVP		0.27
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs760640459; hg19: chr11-2424315;