chr11-78658528-C-T

Position:

chr11-78658528-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_001098816.3(TENM4):c.7840G>A(p.Val2614Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,614,018 control chromosomes in the GnomAD database, including 364 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2614L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 13 hom., cov: 33)

Exomes 𝑓: 0.019 ( 351 hom. )

Consequence

TENM4
NM_001098816.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.445

Variant links:

Genes affected

TENM4 (HGNC:29945): (teneurin transmembrane protein 4) The protein encoded by this gene plays a role in establishing proper neuronal connectivity during development. Defects in this gene have been associated with hereditary essential tremor-5. [provided by RefSeq, Oct 2016]

TENM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TENM4. . Gene score misZ 2.7323 (greater than the threshold 3.09). Trascript score misZ 3.5261 (greater than threshold 3.09). GenCC has associacion of gene with tremor, hereditary essential, 5.

BP4

Computational evidence support a benign effect (MetaRNN=0.008805007).

BP6

Variant 11-78658528-C-T is Benign according to our data. Variant chr11-78658528-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2485392.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2018/152338) while in subpopulation NFE AF= 0.0229 (1557/68018). AF 95% confidence interval is 0.0219. There are 13 homozygotes in gnomad4. There are 899 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2018 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TENM4	NM_001098816.3 linkuse as main transcript	c.7840G>A	p.Val2614Met	missense_variant	34/34	ENST00000278550.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TENM4	ENST00000278550.12 linkuse as main transcript	c.7840G>A	p.Val2614Met	missense_variant	34/34	5	NM_001098816.3	P1
TENM4	ENST00000530738.1 linkuse as main transcript	c.2801-474G>A		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2018

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00960

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0229

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0134

AC:

3332

AN:

249094

Hom.:

AF XY:

0.0131

AC XY:

1772

AN XY:

135154

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.00722

Gnomad ASJ exome

AF:

0.00825

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.0120

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0191

AC:

27858

AN:

1461680

Hom.:

351

Cov.:

AF XY:

0.0186

AC XY:

13552

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00293

Gnomad4 AMR exome

AF:

0.00769

Gnomad4 ASJ exome

AF:

0.00957

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.0117

Gnomad4 NFE exome

AF:

0.0231

Gnomad4 OTH exome

AF:

0.0135

GnomAD4 genome

AF:

0.0132

AC:

2018

AN:

152338

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

899

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00358

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00960

Gnomad4 NFE

AF:

0.0229

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0196

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00391

AC:

ESP6500EA

AF:

0.0184

AC:

155

ExAC

AF:

0.0137

AC:

1658

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0213

EpiControl

AF:

0.0200

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

TENM4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2019

This variant is classified as 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

0.068

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.2

DANN

Benign

0.97

DEOGEN2

Benign

0.071

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0088

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.29

MutationTaster

Benign

0.96

PrimateAI

Benign

0.40

PROVEAN

Benign

1.1

REVEL

Benign

0.13

Sift

Benign

0.10

Sift4G

Benign

0.44

Polyphen

0.0070

Vest4

0.050

MPC

0.28

ClinPred

0.0025

GERP RS

1.8

Varity_R

0.029

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over