rs1135715

Positions:

• chr8-74364724-A-G
• chr8-74364724-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018972.4(GDAP1):​c.*357A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 467,504 control chromosomes in the GnomAD database, including 11,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (2941 hom., cov: 32)
  • Exomes 𝑓: 0.21 (8170 hom.)
• Consequence: GDAP1 NM_018972.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.17

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-74364724-A-G is Benign according to our data. Variant chr8-74364724-A-G is described in ClinVar as [Benign]. Clinvar id is 363721.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDAP1	NM_018972.4	c.*357A>G		3_prime_UTR_variant	6/6	ENST00000220822.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDAP1	ENST00000220822.12	c.*357A>G		3_prime_UTR_variant	6/6	1	NM_018972.4	P3

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28494 AN: 152078 Hom.: 2935 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.209

GnomAD3 exomes AF: 0.241 AC: 31399 AN: 130496 Hom.: 4336 AF XY: 0.233 AC XY: 16622 AN XY: 71210

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.277

Gnomad SAS exome AF: 0.250

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.184

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.214 AC: 67427 AN: 315308 Hom.: 8170 Cov.: 0 AF XY: 0.214 AC XY: 38258 AN XY: 178892

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.396

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.277

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.179

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.187 AC: 28502 AN: 152196 Hom.: 2941 Cov.: 32 AF XY: 0.190 AC XY: 14128 AN XY: 74398

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.312

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.285

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.207

Alfa AF: 0.179 Hom.: 688

Bravo AF: 0.200

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease recessive intermediate A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.19
DANN	Benign	0.52

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: rs1135715; hg19: chr8-75276959;