15-51341953-C-T

Position:

chr15-51341953-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181789.4(GLDN):c.269C>T(p.Ala90Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,597,458 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 14 hom. )

Consequence

GLDN
NM_181789.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.17

Variant links:

Genes affected

GLDN (HGNC:29514): (gliomedin) This gene encodes a protein that contains olfactomedin-like and collagen-like domains. The encoded protein, which exists in both transmembrane and secreted forms, promotes formation of the nodes of Ranvier in the peripheral nervous system. Mutations in this gene cause a form of lethal congenital contracture syndrome in human patients. Autoantibodies to the encoded protein have been identified in sera form patients with multifocal motor neuropathy. [provided by RefSeq, May 2017]

GLDN links:

GLDN (HGNC:):

GLDN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009518027).

BP6

Variant 15-51341953-C-T is Benign according to our data. Variant chr15-51341953-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 546754.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00276 (421/152378) while in subpopulation NFE AF= 0.00413 (281/68032). AF 95% confidence interval is 0.00373. There are 0 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDN	NM_181789.4 linkuse as main transcript	c.269C>T	p.Ala90Val	missense_variant	1/10	ENST00000335449.11	NP_861454.2	Q6ZMI3-1
GLDN	XM_017022121.2 linkuse as main transcript	c.269C>T	p.Ala90Val	missense_variant	1/9		XP_016877610.1
GLDN	XM_017022125.1 linkuse as main transcript	c.269C>T	p.Ala90Val	missense_variant	1/10		XP_016877614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GLDN	ENST00000335449.11 linkuse as main transcript	c.269C>T	p.Ala90Val	missense_variant	1/10	2	NM_181789.4	ENSP00000335196.6	Q6ZMI3-1
GLDN	ENST00000558286.5 linkuse as main transcript	n.80C>T		non_coding_transcript_exon_variant	1/3	1
GLDN	ENST00000560690.5 linkuse as main transcript	n.8C>T		non_coding_transcript_exon_variant	1/4	1
GLDN	ENST00000560215.5 linkuse as main transcript	c.155C>T	p.Ala52Val	missense_variant	1/4	4		ENSP00000484633.1	A0A087X220

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

421

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00734

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00413

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00313

AC:

703

AN:

224646

Hom.:

AF XY:

0.00322

AC XY:

401

AN XY:

124422

show subpopulations

Gnomad AFR exome

AF:

0.000786

Gnomad AMR exome

AF:

0.000673

Gnomad ASJ exome

AF:

0.00135

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00161

Gnomad FIN exome

AF:

0.00861

Gnomad NFE exome

AF:

0.00478

Gnomad OTH exome

AF:

0.00367

GnomAD4 exome

AF:

0.00378

AC:

5459

AN:

1445080

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

2730

AN XY:

719296

show subpopulations

Gnomad4 AFR exome

AF:

0.000419

Gnomad4 AMR exome

AF:

0.000739

Gnomad4 ASJ exome

AF:

0.00157

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00165

Gnomad4 FIN exome

AF:

0.0101

Gnomad4 NFE exome

AF:

0.00419

Gnomad4 OTH exome

AF:

0.00302

GnomAD4 genome

AF:

0.00276

AC:

421

AN:

152378

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

211

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00734

Gnomad4 NFE

AF:

0.00413

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00262

Hom.:

Bravo

AF:

0.00243

ESP6500AA

AF:

0.000252

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00365

AC:

429

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -

GLDN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 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

0.15

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0095

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.20

REVEL

Benign

0.28

Sift

Benign

0.10

Sift4G

Benign

0.11

Polyphen

0.79

Vest4

0.40

MVP

0.82

MPC

0.20

ClinPred

0.012

GERP RS

3.8

Varity_R

0.082

gMVP

0.55

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