11-2402950-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005706.4(TSSC4):c.317G>A(p.Arg106Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,610,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: TSSC4 NM_005706.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.690

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0041026473).
• BP6: Variant 11-2402950-G-A is Benign according to our data. Variant chr11-2402950-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2352657.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSSC4	NM_005706.4	c.317G>A	p.Arg106Gln	missense_variant	3/3	ENST00000333256.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSSC4	ENST00000333256.11	c.317G>A	p.Arg106Gln	missense_variant	3/3	1	NM_005706.4	P2

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000522 AC: 127 AN: 243062 Hom.: 0 AF XY: 0.000529 AC XY: 70 AN XY: 132366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.000595

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000479 AC: 699 AN: 1458454 Hom.: 1 Cov.: 30 AF XY: 0.000480 AC XY: 348 AN XY: 725260

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.000488

Gnomad4 OTH exome AF: 0.000465

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74492

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000364 AC: 44

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.61
Dann	Benign	0.74
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.66	T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0041	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.62	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.011
Sift	Benign	0.77	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T;T;T;T
Polyphen		0.017	B;B;.;.;.;.;.;.;B
Vest4		0.041
MVP		0.040
MPC		0.017
ClinPred		0.0074	T
GERP RS		-0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.12

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: rs137872687; hg19: chr11-2424180;