X-124381186-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The ENST00000422452.4(TENM1):c.7549G>A(p.Gly2517Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,207,961 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 249 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00040 (0 hom. 238 hem.)
• Consequence: TENM1 ENST00000422452.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.09

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TENM1
• BP4: Computational evidence support a benign effect (MetaRNN=0.006038189).
• BP6: Variant X-124381186-C-T is Benign according to our data. Variant chrX-124381186-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3052802.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TENM1	NM_001163278.2	c.7549G>A	p.Gly2517Arg	missense_variant	35/35	ENST00000422452.4
TENM1	XM_017029210.3	c.7648G>A	p.Gly2550Arg	missense_variant	35/35
LOC105373331	XR_938576.1	n.88+192C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TENM1	ENST00000422452.4	c.7549G>A	p.Gly2517Arg	missense_variant	35/35	1	NM_001163278.2	A1
TENM1	ENST00000371130.7	c.7528G>A	p.Gly2510Arg	missense_variant	31/31	1		P4
STAG2	ENST00000469481.1	n.454-30636C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000187 AC: 21 AN: 112062 Hom.: 0 Cov.: 23 AF XY: 0.000292 AC XY: 10 AN XY: 34226

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000944

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.000661

GnomAD3 exomes AF: 0.000639 AC: 115 AN: 180062 Hom.: 0 AF XY: 0.00113 AC XY: 74 AN XY: 65696

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00540

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000986

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.000401 AC: 439 AN: 1095845 Hom.: 0 Cov.: 31 AF XY: 0.000657 AC XY: 238 AN XY: 362117

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: 0.00598

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000962

Gnomad4 OTH exome AF: 0.000239

GnomAD4 genome AF: 0.000196 AC: 22 AN: 112116 Hom.: 0 Cov.: 23 AF XY: 0.000321 AC XY: 11 AN XY: 34290

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.0000943

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00558

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000752

Gnomad4 OTH AF: 0.000652

Alfa AF: 0.000213 Hom.: 1

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00101 AC: 122

EpiCase AF: 0.000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TENM1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Benign	0.95
DEOGEN2	Benign	0.025	T;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.41	N;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.96	N;N
REVEL	Benign	0.18
Sift	Benign	0.11	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.12	B;.
Vest4		0.098
MutPred		0.33		Gain of solvent accessibility (P = 0.019);.;
MVP		0.44
MPC		0.58
ClinPred		0.025	T
GERP RS		5.8
Varity_R		0.26
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs185277810; hg19: chrX-123515036;