X-124380950-G-C

Position:

• chrX-124380950-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001163278.2(TENM1):​c.7785C>G​(p.Ile2595Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,949 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: TENM1 NM_001163278.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.98

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]

LOC105373331 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18538177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TENM1	NM_001163278.2	c.7785C>G	p.Ile2595Met	missense_variant	35/35		NP_001156750.1
TENM1	NM_001163279.1	c.7782C>G	p.Ile2594Met	missense_variant	32/32		NP_001156751.1
TENM1	NM_014253.3	c.7764C>G	p.Ile2588Met	missense_variant	31/31		NP_055068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TENM1	ENST00000371130.7	c.7764C>G	p.Ile2588Met	missense_variant	31/31	1		ENSP00000360171.3
TENM1	ENST00000422452.3	c.7731C>G	p.Ile2577Met	missense_variant	35/35	1		ENSP00000403954.4
STAG2	ENST00000469481.1	n.454-30872G>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097949 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363343

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000529

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

Nov 15, 2024

The c.7785C>G (p.I2595M) alteration is located in exon 32 (coding exon 32) of the TENM1 gene. This alteration results from a C to G substitution at nucleotide position 7785, causing the isoleucine (I) at amino acid position 2595 to be replaced by a methionine (M). 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	0.089
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	0.72
DANN	Benign	0.96
DEOGEN2	Benign	0.078	T;.
FATHMM_MKL	Benign	0.065	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.51	N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.99	D;.
Vest4		0.46
MutPred		0.41		Loss of sheet (P = 0.0126);.;
MVP		0.67
MPC		0.91
ClinPred		0.59	D
GERP RS		-8.5
Varity_R		0.15
gMVP		0.57

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: rs1340748292; hg19: chrX-123514800;