7-130672749-C-T

Variant names:

• chr7-130672749-C-T
• rs557505484
• NM_052933.4:c.515G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052933.4(TSGA13):​c.515G>A​(p.Arg172Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TSGA13 NM_052933.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.09
• Publications: 4 publications found

Genes affected

TSGA13 (HGNC:12369): (testis specific 13)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046648026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSGA13	NM_052933.4	c.515G>A	p.Arg172Gln	missense_variant	Exon 6 of 8	ENST00000356588.8	NP_443165.1
TSGA13	NM_001304968.2	c.515G>A	p.Arg172Gln	missense_variant	Exon 7 of 9		NP_001291897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSGA13	ENST00000356588.8	c.515G>A	p.Arg172Gln	missense_variant	Exon 6 of 8	1	NM_052933.4	ENSP00000348996.3
TSGA13	ENST00000456951.5	c.515G>A	p.Arg172Gln	missense_variant	Exon 7 of 9	2		ENSP00000406047.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 32

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250426 AF XY: 0.00000739

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460898 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726796

African (AFR) AF: 0.0000299 AC: 1 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111520

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74484

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000034), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.515G>A (p.R172Q) alteration is located in exon 6 (coding exon 5) of the TSGA13 gene. This alteration results from a G to A substitution at nucleotide position 515, causing the arginine (R) at amino acid position 172 to be replaced by a glutamine (Q). 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	Benign	0.090
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.029
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.64	.;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
PhyloP100		-3.1
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.082
Sift	Benign	0.27	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.21	B;B
Vest4		0.12
MutPred		0.14		Loss of phosphorylation at S170 (P = 0.0815);Loss of phosphorylation at S170 (P = 0.0815);
MVP		0.095
MPC		0.27
ClinPred		0.088	T
GERP RS		-6.2
Varity_R		0.046
gMVP		0.039
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs557505484; hg19: chr7-130357589; COSMIC: COSV104401645; COSMIC: COSV104401645;