rs863224774

Positions:

• chr8-74351325-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_018972.4(GDAP1):​c.169A>C​(p.Ser57Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GDAP1 NM_018972.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.67

Genes affected

GDAP1 (HGNC:15968): (ganglioside induced differentiation associated protein 1) This gene encodes a member of the ganglioside-induced differentiation-associated protein family, which may play a role in a signal transduction pathway during neuronal development. Mutations in this gene have been associated with various forms of Charcot-Marie-Tooth Disease and neuropathy. Two transcript variants encoding different isoforms and a noncoding variant have been identified for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain GST N-terminal (size 81) in uniprot entity GDAP1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_018972.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-74351325-A-C is Pathogenic according to our data. Variant chr8-74351325-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216706.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.169A>C	p.Ser57Arg	missense_variant	2/6	ENST00000220822.12	NP_061845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12	c.169A>C	p.Ser57Arg	missense_variant	2/6	1	NM_018972.4	ENSP00000220822.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease type 4A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 216706). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 57 of the GDAP1 protein (p.Ser57Arg). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.48
MutPred		0.48		Loss of disorder (P = 0.066);
MVP		0.89
MPC		0.94
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.70
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs863224774; hg19: chr8-75263560;