rs6472842

chr8-74366222-A-Gchr8-74366222-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018972.4(GDAP1):c.*1855A>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 0.296 in 453,828 control chromosomes in the GnomAD database, including 20,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7054 hom., cov: 32)
  • Exomes 𝑓: 0.29 (13893 hom.)
• Consequence: GDAP1 NM_018972.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.23

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-74366222-A-G is Benign according to our data. Variant chr8-74366222-A-G is described in ClinVar as [Benign]. Clinvar id is 363752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDAP1	NM_018972.4	c.*1855A>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.*1855A>G		3_prime_UTR_variant	6/6	1	NM_018972.4	P3

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45577 AN: 151950 Hom.: 7053 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.312

GnomAD3 exomes AF: 0.283 AC: 38461 AN: 135968 Hom.: 5826 AF XY: 0.283 AC XY: 20891 AN XY: 73764

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.330

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.294 AC: 88866 AN: 301760 Hom.: 13893 Cov.: 0 AF XY: 0.288 AC XY: 49504 AN XY: 171930

Gnomad4 AFR exome AF: 0.256

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.290

Gnomad4 EAS exome AF: 0.325

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.300 AC: 45616 AN: 152068 Hom.: 7054 Cov.: 32 AF XY: 0.299 AC XY: 22201 AN XY: 74310

Gnomad4 AFR AF: 0.256

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.314

Alfa AF: 0.309 Hom.: 2712

Bravo AF: 0.293

Asia WGS AF: 0.265 AC: 922 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.55
Dann	Benign	0.38

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: rs6472842; hg19: chr8-75278457; COSMIC: COSV55185002; COSMIC: COSV55185002;