15-51341779-C-T

Variant names:

• chr15-51341779-C-T
• rs779432560
• NM_181789.4:c.95C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_181789.4(GLDN):​c.95C>T​(p.Ala32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000334 in 1,498,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A32E) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GLDN NM_181789.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-51341779-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.14721492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDN	NM_181789.4	c.95C>T	p.Ala32Val	missense_variant	Exon 1 of 10	ENST00000335449.11	NP_861454.2
GLDN	XM_017022121.2	c.95C>T	p.Ala32Val	missense_variant	Exon 1 of 9		XP_016877610.1
GLDN	XM_017022125.1	c.95C>T	p.Ala32Val	missense_variant	Exon 1 of 10		XP_016877614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDN	ENST00000335449.11	c.95C>T	p.Ala32Val	missense_variant	Exon 1 of 10	2	NM_181789.4	ENSP00000335196.6
GLDN	ENST00000558286.5	n.-95C>T		upstream_gene_variant		1
GLDN	ENST00000560690.5	n.-167C>T		upstream_gene_variant		1
GLDN	ENST00000560215.5	c.-20C>T		upstream_gene_variant		4		ENSP00000484633.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1346000 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 663894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.39e-7

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.46	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.17
Sift	Benign	0.76	T
Sift4G	Benign	0.45	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.62		Gain of sheet (P = 0.0266);
MVP		0.44
MPC		1.8
ClinPred		0.24	T
GERP RS		-1.6
Varity_R		0.11
gMVP		0.59

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: rs779432560; hg19: chr15-51633976;