rs146419593

Variant names:

• chrX-124380579-T-C
• rs146419593
• NM_001163278.2:c.8156A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001163278.2(TENM1):​c.8156A>G​(p.Asn2719Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000312 in 1,208,812 control chromosomes in the GnomAD database, including 2 homozygotes. There are 89 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., 41 hem., cov: 23)
  • Exomes 𝑓: 0.00019 (1 hom. 48 hem.)
• Consequence: TENM1 NM_001163278.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.10
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010320634).
• BP6: Variant X-124380579-T-C is Benign according to our data. Variant chrX-124380579-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3042360.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 173 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163278.2. 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.8156A>G	p.Asn2719Ser	missense	Exon 35 of 35	NP_001156750.1	Q9UKZ4-2
	TENM1	NM_001163279.1		c.8153A>G	p.Asn2718Ser	missense	Exon 32 of 32	NP_001156751.1	B7ZMH4
	TENM1	NM_014253.3		c.8135A>G	p.Asn2712Ser	missense	Exon 31 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.8156A>G	p.Asn2719Ser	missense	Exon 35 of 35	ENSP00000403954.4	Q9UKZ4-2
	TENM1	ENST00000371130.7	TSL:1	c.8135A>G	p.Asn2712Ser	missense	Exon 31 of 31	ENSP00000360171.3	Q9UKZ4-1
	STAG2	ENST00000469481.1	TSL:3	n.454-31243T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 173 AN: 112081 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.00545

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

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: 0.0000375

Gnomad OTH AF: 0.000662

GnomAD2 exomes AF: 0.000428 AC: 77 AN: 179779 AF XY: 0.000263

Gnomad AFR exome AF: 0.00533

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.000186 AC: 204 AN: 1096678 Hom.: 1 Cov.: 29 AF XY: 0.000133 AC XY: 48 AN XY: 362224

African (AFR) AF: 0.00668 AC: 176 AN: 26365

American (AMR) AF: 0.000257 AC: 9 AN: 35075

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19276

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 53850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4115

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841296

Other (OTH) AF: 0.000326 AC: 15 AN: 46028

GnomAD4 genome AF: 0.00154 AC: 173 AN: 112134 Hom.: 1 Cov.: 23 AF XY: 0.00120 AC XY: 41 AN XY: 34304

African (AFR) AF: 0.00544 AC: 168 AN: 30907

American (AMR) AF: 0.000189 AC: 2 AN: 10596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53264

Other (OTH) AF: 0.000654 AC: 1 AN: 1530

Alfa AF: 0.000698 Hom.: 29

Bravo AF: 0.00180

ESP6500AA AF: 0.00678 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000387 AC: 47

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TENM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.042	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.52	N
PhyloP100		4.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Benign	0.50	T
Sift4G	Benign	0.42	T
Polyphen		0.013	B
Vest4		0.25
MVP		0.63
MPC		0.37
ClinPred		0.026	T
GERP RS		5.7
Varity_R		0.17
gMVP		0.17
Mutation Taster		=96/4	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: rs146419593; hg19: chrX-123514429; COSMIC: COSV99058416;