chrX-124380579-T-C

Position:

• chrX-124380579-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The ENST00000422452.4(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. 12/20 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 ENST00000422452.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.10

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• 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=0.010320634).
• 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 id is 3042360.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TENM1	NM_001163278.2	c.8156A>G	p.Asn2719Ser	missense_variant	35/35	ENST00000422452.4	NP_001156750.1
TENM1	XM_017029210.3	c.8255A>G	p.Asn2752Ser	missense_variant	35/35		XP_016884699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TENM1	ENST00000422452.4	c.8156A>G	p.Asn2719Ser	missense_variant	35/35	1	NM_001163278.2	ENSP00000403954	A1
TENM1	ENST00000371130.7	c.8135A>G	p.Asn2712Ser	missense_variant	31/31	1		ENSP00000360171	P4
STAG2	ENST00000469481.1	n.454-31243T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 173 AN: 112081 Hom.: 1 Cov.: 23 AF XY: 0.00120 AC XY: 41 AN XY: 34241

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

GnomAD3 exomes AF: 0.000428 AC: 77 AN: 179779 Hom.: 0 AF XY: 0.000263 AC XY: 17 AN XY: 64571

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 SAS 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

Gnomad4 AFR exome AF: 0.00668

Gnomad4 AMR exome AF: 0.000257

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: 0.00000475

Gnomad4 OTH exome AF: 0.000326

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

Gnomad4 AFR AF: 0.00544

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000375

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.000166 Hom.: 3

Bravo AF: 0.00180

ESP6500AA AF: 0.00678 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000387 AC: 47

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TENM1-related disorder Benign:1

Likely benign, no assertion criteria provided

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	0.062
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;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.52	N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.23
Sift	Benign	0.50	T;T
Sift4G	Benign	0.42	T;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

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: rs146419593; hg19: chrX-123514429; COSMIC: COSV99058416;