X-124380950-G-C

Position:

• chrX-124380950-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TENM1. . Gene score misZ 3.4329 (greater than the threshold 3.09). GenCC has associacion of gene with anosmia, cerebral palsy, isolated congenital anosmia.
• 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;