Genetic Variant ENST00000371130.7:c.7321G>A (chrX-124382768-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000371130.7(TENM1):c.7321G>A(p.Val2441Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000916 in 1,091,787 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Consequence

TENM1
ENST00000371130.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.12

Variant links:

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]

TENM1 links:

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]

STAG2 links:

LOC105373331 (HGNC:):

LOC105373331 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
TENM1	NM_001163278.2 link	c.7342G>A	p.Val2448Ile	missense_variant	Exon 34 of 35	NP_001156750.1	Q9UKZ4-2
TENM1	NM_001163279.1 link	c.7339G>A	p.Val2447Ile	missense_variant	Exon 31 of 32	NP_001156751.1	Q9UKZ4B7ZMH4
TENM1	NM_014253.3 link	c.7321G>A	p.Val2441Ile	missense_variant	Exon 30 of 31	NP_055068.2	Q9UKZ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
TENM1	ENST00000371130.7 link	c.7321G>A	p.Val2441Ile	missense_variant	Exon 30 of 31	1	ENSP00000360171.3	Q9UKZ4-1
TENM1	ENST00000422452.3 link	c.7288G>A	p.Val2430Ile	missense_variant	Exon 34 of 35	1	ENSP00000403954.4	A0A8Z5AZJ6
STAG2	ENST00000469481.1 link	n.454-29054C>T		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.16e-7

AC:

AN:

1091787

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

357843

show subpopulations

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:

0.0000189

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7342G>A (p.V2448I) alteration is located in exon 31 (coding exon 31) of the TENM1 gene. This alteration results from a G to A substitution at nucleotide position 7342, causing the valine (V) at amino acid position 2448 to be replaced by an isoleucine (I). 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

0.091

BayesDel_addAF

Benign

-0.0023

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Uncertain

-0.041

MutationAssessor

Benign

1.0

L;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.50

N;N

REVEL

Uncertain

0.35

Sift

Benign

0.58

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.98

D;.

Vest4

0.28

MutPred

0.29

Loss of sheet (P = 0.0457);.;

MVP

0.68

MPC

0.54

ClinPred

0.82

GERP RS

5.5

Varity_R

0.15

gMVP

0.53

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over