7-116250419-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015641.4(TES):c.625C>T(p.Pro209Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,611,216 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: TES NM_015641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.886

Genes affected

TES (HGNC:14620): (testin LIM domain protein) Cancer-associated chromosomal changes often involve regions containing fragile sites. This gene maps to a common fragile site on chromosome 7q31.2 designated FRA7G. This gene is similar to mouse Testin, a testosterone-responsive gene encoding a Sertoli cell secretory protein containing three LIM domains. LIM domains are double zinc-finger motifs that mediate protein-protein interactions between transcription factors, cytoskeletal proteins and signaling proteins. This protein is a negative regulator of cell growth and may act as a tumor suppressor. This scaffold protein may also play a role in cell adhesion, cell spreading and in the reorganization of the actin cytoskeleton. Multiple protein isoforms are encoded by transcript variants of this gene.[provided by RefSeq, Aug 2023]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025094092).
• BS2: High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TES	NM_015641.4	c.625C>T	p.Pro209Ser	missense_variant	4/7	ENST00000358204.9
LOC124901730	XR_007060484.1	n.2187+4699G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TES	ENST00000358204.9	c.625C>T	p.Pro209Ser	missense_variant	4/7	1	NM_015641.4	P1
	ENST00000444244.1	n.183+4699G>A		intron_variant, non_coding_transcript_variant		3
	ENST00000446355.2	n.204-6483G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000169 AC: 42 AN: 247812 Hom.: 0 AF XY: 0.000179 AC XY: 24 AN XY: 133922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000712

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000131 AC: 191 AN: 1458900 Hom.: 1 Cov.: 31 AF XY: 0.000120 AC XY: 87 AN XY: 725634

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000722

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74492

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000917 Hom.: 0

Bravo AF: 0.000291

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000549

EpiControl AF: 0.000120

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.625C>T (p.P209S) alteration is located in exon 4 (coding exon 4) of the TES gene. This alteration results from a C to T substitution at nucleotide position 625, causing the proline (P) at amino acid position 209 to be replaced by a serine (S). 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	0.068
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.064
Sift	Benign	0.048	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.019	B;.
Vest4		0.089
MVP		0.59
MPC		0.069
ClinPred		0.0075	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.23

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: rs188977232; hg19: chr7-115890473;