ENST00000371130.7:c.6512G>A

Variant names:

• chrX-124384398-C-T
• rs762426434
• NM_001163278.2:c.6533G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000371130.7(TENM1):​c.6512G>A​(p.Arg2171His) variant causes a missense change. The variant allele was found at a frequency of 0.0000314 in 1,209,013 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2171C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000034 (0 hom. 13 hem.)
• Consequence: TENM1 ENST00000371130.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17
• Publications: 5 publications found

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]

STAG2 Gene-Disease associations (from GenCC):

• Mullegama-Klein-Martinez syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Xq25 microduplication syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

LOC105373331 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 37 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371130.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENM1	NM_001163278.2	MANE Select	c.6533G>A	p.Arg2178His	missense	Exon 33 of 35	NP_001156750.1	Q9UKZ4-2
	TENM1	NM_001163279.1		c.6530G>A	p.Arg2177His	missense	Exon 30 of 32	NP_001156751.1	B7ZMH4
	TENM1	NM_014253.3		c.6512G>A	p.Arg2171His	missense	Exon 29 of 31	NP_055068.2	Q9UKZ4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENM1	ENST00000422452.4	TSL:1 MANE Select	c.6533G>A	p.Arg2178His	missense	Exon 33 of 35	ENSP00000403954.4	Q9UKZ4-2
	TENM1	ENST00000371130.7	TSL:1	c.6512G>A	p.Arg2171His	missense	Exon 29 of 31	ENSP00000360171.3	Q9UKZ4-1
	STAG2	ENST00000469481.1	TSL:3	n.454-27424C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000901 AC: 1 AN: 110958 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000547 AC: 10 AN: 182974 AF XY: 0.0000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000337 AC: 37 AN: 1098055 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 13 AN XY: 363445

African (AFR) AF: 0.0000379 AC: 1 AN: 26400

American (AMR) AF: 0.0000852 AC: 3 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.0000924 AC: 5 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40503

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000285 AC: 24 AN: 842005

Other (OTH) AF: 0.0000868 AC: 4 AN: 46092

GnomAD4 genome AF: 0.00000901 AC: 1 AN: 110958 Hom.: 0 Cov.: 23 AF XY: 0.0000301 AC XY: 1 AN XY: 33186

African (AFR) AF: 0.00 AC: 0 AN: 30476

American (AMR) AF: 0.00 AC: 0 AN: 10457

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2567

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5959

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52901

Other (OTH) AF: 0.00 AC: 0 AN: 1481

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.52		Loss of ubiquitination at K2167 (P = 0.0683)
MVP		0.91
MPC		1.5
ClinPred		0.63	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.49
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs762426434; hg19: chrX-123518248; COSMIC: COSV64428703;