rs121908114

chr8-74363051-C-Gchr8-74363051-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_018972.4(GDAP1):c.692C>G(p.Pro231Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P231L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: GDAP1 NM_018972.4 missense, splice_region
• Scores: Splicing: ADA: 0.8198
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain GST C-terminal (size 156) in uniprot entity GDAP1_HUMAN there are 54 pathogenic changes around while only 0 benign (100%) in NM_018972.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-74363051-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDAP1	NM_018972.4	c.692C>G	p.Pro231Arg	missense_variant, splice_region_variant	5/6	ENST00000220822.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDAP1	ENST00000220822.12	c.692C>G	p.Pro231Arg	missense_variant, splice_region_variant	5/6	1	NM_018972.4	P3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.013
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.49	N;N
REVEL	Uncertain	0.61
Sift	Benign	0.056	T;D
Sift4G	Benign	0.081	T;T
Polyphen		0.11	B;.
Vest4		0.57
MutPred		0.45		Loss of loop (P = 0.0512);.;
MVP		0.99
MPC		1.3
ClinPred		0.84	D
GERP RS		4.8
Varity_R		0.24
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.52
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: rs121908114; hg19: chr8-75275286;