15-51404521-G-T

Variant names:

• chr15-51404521-G-T
• rs764239923
• NM_181789.4:c.1423G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_181789.4(GLDN):​c.1423G>T​(p.Ala475Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A475P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GLDN NM_181789.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 11

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-51404521-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 268105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181789.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDN	NM_181789.4	MANE Select	c.1423G>T	p.Ala475Ser	missense	Exon 10 of 10	NP_861454.2	Q6ZMI3-1
	GLDN	NM_001330297.2		c.1051G>T	p.Ala351Ser	missense	Exon 10 of 10	NP_001317226.1	Q6ZMI3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDN	ENST00000335449.11	TSL:2 MANE Select	c.1423G>T	p.Ala475Ser	missense	Exon 10 of 10	ENSP00000335196.6	Q6ZMI3-1
	GLDN	ENST00000396399.6	TSL:1	c.1051G>T	p.Ala351Ser	missense	Exon 10 of 10	ENSP00000379681.2	Q6ZMI3-2
	GLDN	ENST00000857823.1		c.1405G>T	p.Ala469Ser	missense	Exon 9 of 9	ENSP00000527882.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.90		Gain of disorder (P = 0.0357)
MVP		0.99
MPC		0.52
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.76
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs764239923; hg19: chr15-51696718;