15-51341953-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.17

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]

ACMG classification

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: {Benign=2, Uncertain_significance=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 GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDN	NM_181789.4	c.269C>T	p.Ala90Val	missense_variant	1/10	ENST00000335449.11
GLDN	XM_017022121.2	c.269C>T	p.Ala90Val	missense_variant	1/9
GLDN	XM_017022125.1	c.269C>T	p.Ala90Val	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDN	ENST00000335449.11	c.269C>T	p.Ala90Val	missense_variant	1/10	2	NM_181789.4	P1
GLDN	ENST00000558286.5	n.80C>T		non_coding_transcript_exon_variant	1/3	1
GLDN	ENST00000560690.5	n.8C>T		non_coding_transcript_exon_variant	1/4	1
GLDN	ENST00000560215.5	c.158C>T	p.Ala53Val	missense_variant	1/4	4

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 421 AN: 152260 Hom.: 0 Cov.: 33

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.: 2 AF XY: 0.00322 AC XY: 401 AN XY: 124422

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.: 14 Cov.: 30 AF XY: 0.00380 AC XY: 2730 AN XY: 719296

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.: 0 Cov.: 33 AF XY: 0.00283 AC XY: 211 AN XY: 74522

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.: 0

Bravo AF: 0.00243

ESP6500AA AF: 0.000252 AC: 1

ESP6500EA AF: 0.00302 AC: 25

ExAC AF: 0.00365 AC: 429

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0095	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.62	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.28
Sift	Benign	0.10	T
Sift4G	Benign	0.11	T
Polyphen		0.79	P
Vest4		0.40
MVP		0.82
MPC		0.20
ClinPred		0.012	T
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

Other links and lift over

dbSNP: rs186935606; hg19: chr15-51634150;