X-124381101-T-A

Variant names:

• chrX-124381101-T-A
• rs1295657021
• ENST00000371130.7:c.7613A>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001163278.2(TENM1):​c.7634A>T​(p.Asp2545Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,097,648 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: TENM1 NM_001163278.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

TENM1 (HGNC:8117): (teneurin transmembrane protein 1) The protein encoded by this gene belongs to the tenascin family and teneurin subfamily. It is expressed in the neurons and may function as a cellular signal transducer. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

STAG2 (HGNC:11355): (STAG2 cohesin complex component) The protein encoded by this gene is a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Targeted inactivation of this gene results in chromatid cohesion defects and aneuploidy, suggesting that genetic disruption of cohesin is a cause of aneuploidy in human cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

LOC105373331 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833
• BS2: High Hemizygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TENM1	NM_001163278.2	c.7634A>T	p.Asp2545Val	missense_variant	Exon 35 of 35		NP_001156750.1
TENM1	NM_001163279.1	c.7631A>T	p.Asp2544Val	missense_variant	Exon 32 of 32		NP_001156751.1
TENM1	NM_014253.3	c.7613A>T	p.Asp2538Val	missense_variant	Exon 31 of 31		NP_055068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TENM1	ENST00000371130.7	c.7613A>T	p.Asp2538Val	missense_variant	Exon 31 of 31	1		ENSP00000360171.3
TENM1	ENST00000422452.3	c.7580A>T	p.Asp2527Val	missense_variant	Exon 35 of 35	1		ENSP00000403954.4
STAG2	ENST00000469481.1	n.454-30721T>A		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182379 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67113

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 SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1097648 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 3 AN XY: 363060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7634A>T (p.D2545V) alteration is located in exon 32 (coding exon 32) of the TENM1 gene. This alteration results from a A to T substitution at nucleotide position 7634, causing the aspartic acid (D) at amino acid position 2545 to be replaced by a valine (V). 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	0.33
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.93	P;.
Vest4		0.63
MutPred		0.50		Gain of sheet (P = 0.0028);.;
MVP		0.67
MPC		0.68
ClinPred		0.68	D
GERP RS		5.8
Varity_R		0.77
gMVP		0.83

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: rs1295657021; hg19: chrX-123514951;