11-2403004-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005706.4(TSSC4):c.371G>A(p.Arg124Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,607,978 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (31 hom.)
• Consequence: TSSC4 NM_005706.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.421

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021829903).
• BP6: Variant 11-2403004-G-A is Benign according to our data. Variant chr11-2403004-G-A is described in ClinVar as [Benign]. Clinvar id is 768414.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1626/152318) while in subpopulation AFR AF= 0.0375 (1558/41558). AF 95% confidence interval is 0.0359. There are 24 homozygotes in gnomad4. There are 758 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSSC4	NM_005706.4	c.371G>A	p.Arg124Gln	missense_variant	3/3	ENST00000333256.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSSC4	ENST00000333256.11	c.371G>A	p.Arg124Gln	missense_variant	3/3	1	NM_005706.4	P2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1624 AN: 152200 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

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: 0.00382

GnomAD3 exomes AF: 0.00261 AC: 617 AN: 236406 Hom.: 14 AF XY: 0.00186 AC XY: 241 AN XY: 129238

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000674

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000379

Gnomad OTH exome AF: 0.000860

GnomAD4 exome AF: 0.00102 AC: 1490 AN: 1455660 Hom.: 31 Cov.: 30 AF XY: 0.000907 AC XY: 656 AN XY: 723622

Gnomad4 AFR exome AF: 0.0371

Gnomad4 AMR exome AF: 0.00176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000935

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00241

GnomAD4 genome AF: 0.0107 AC: 1626 AN: 152318 Hom.: 24 Cov.: 33 AF XY: 0.0102 AC XY: 758 AN XY: 74476

Gnomad4 AFR AF: 0.0375

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.0296 Hom.: 2356

Bravo AF: 0.0121

ESP6500AA AF: 0.0314 AC: 138

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00324 AC: 391

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	1.4
Dann	Benign	0.85
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.72	T;.;T;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.41	T;T;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T;T
Polyphen		0.086	B;B;.;.;.;.;B
Vest4		0.12
MVP		0.014
MPC		0.017
ClinPred		0.0014	T
GERP RS		-3.6
Varity_R		0.020
gMVP		0.30

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: rs1008265; hg19: chr11-2424234;