rs6472842

Variant names:

• chr8-74366222-A-G
• rs6472842
• NM_018972.4:c.*1855A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-74366222-A-G
• chr8-74366222-A-T

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -1.23
• Publications: 7 publications found

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]

GDAP1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2K

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease recessive intermediate A

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant Charcot-Marie-Tooth disease type 2K

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 4A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.*1855A>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000220822.12	NP_061845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12	c.*1855A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_018972.4	ENSP00000220822.7

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

GnomAD2 exomes AF: 0.283 AC: 38461 AN: 135968 AF XY: 0.283

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 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

African (AFR) AF: 0.256 AC: 2192 AN: 8548

American (AMR) AF: 0.203 AC: 5524 AN: 27206

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 3123 AN: 10776

East Asian (EAS) AF: 0.325 AC: 2995 AN: 9210

South Asian (SAS) AF: 0.210 AC: 12483 AN: 59388

European-Finnish (FIN) AF: 0.339 AC: 4340 AN: 12784

Middle Eastern (MID) AF: 0.267 AC: 307 AN: 1148

European-Non Finnish (NFE) AF: 0.338 AC: 53574 AN: 158670

Other (OTH) AF: 0.308 AC: 4328 AN: 14030

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

African (AFR) AF: 0.256 AC: 10626 AN: 41488

American (AMR) AF: 0.254 AC: 3882 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1066 AN: 3470

East Asian (EAS) AF: 0.312 AC: 1614 AN: 5168

South Asian (SAS) AF: 0.212 AC: 1021 AN: 4816

European-Finnish (FIN) AF: 0.333 AC: 3512 AN: 10562

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22866 AN: 67964

Other (OTH) AF: 0.314 AC: 665 AN: 2116

Alfa AF: 0.311 Hom.: 4386

Bravo AF: 0.293

Asia WGS AF: 0.265 AC: 922 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.84
CADD	Benign	0.55
DANN	Benign	0.38
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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