chr11-2402827-C-T

Variant names:

• chr11-2402827-C-T
• rs769354699
• NM_005706.4:c.194C>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.194C>T​(p.Pro65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000094 in 1,596,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: TSSC4 NM_005706.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.368
• Publications: 1 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=0.080430984).

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.194C>T	p.Pro65Leu	missense	Exon 3 of 3	NP_005697.2
	TSSC4	NM_001297658.2		c.194C>T	p.Pro65Leu	missense	Exon 4 of 4	NP_001284587.1	Q9Y5U2-1
	TSSC4	NM_001297659.2		c.194C>T	p.Pro65Leu	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.194C>T	p.Pro65Leu	missense	Exon 3 of 3	ENSP00000331087.6	Q9Y5U2-1
	TSSC4	ENST00000451491.2	TSL:1	c.194C>T	p.Pro65Leu	missense	Exon 2 of 2	ENSP00000411224.2	Q9Y5U2-1
	TSSC4	ENST00000496468.1	TSL:1	c.194C>T	p.Pro65Leu	missense	Exon 2 of 2	ENSP00000435013.1	E9PME3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000269 AC: 6 AN: 222990 AF XY: 0.0000413

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: 0.0000509

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000969 AC: 14 AN: 1444408 Hom.: 0 Cov.: 30 AF XY: 0.0000112 AC XY: 8 AN XY: 717046

African (AFR) AF: 0.0000302 AC: 1 AN: 33144

American (AMR) AF: 0.00 AC: 0 AN: 43370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 38964

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000997 AC: 11 AN: 1103374

Other (OTH) AF: 0.0000168 AC: 1 AN: 59628

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000829 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	0.079
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.37
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.10
Sift	Benign	0.13	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.12
MutPred		0.16		Loss of glycosylation at P65 (P = 0.0189)
MVP		0.17
MPC		0.030
ClinPred		0.085	T
GERP RS		2.2
Varity_R		0.018
gMVP		0.090
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs769354699; hg19: chr11-2424057; COSMIC: COSV104548816; COSMIC: COSV104548816;