chr8-74364724-A-G

Variant names:

• chr8-74364724-A-G
• rs1135715
• NM_018972.4:c.*357A>G

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.*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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.17
• Publications: 5 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=-0.88).
• BP6: Variant 8-74364724-A-G is Benign according to our data. Variant chr8-74364724-A-G is described in ClinVar as Benign. ClinVar VariationId is 363721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.*357A>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.*357A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_018972.4	ENSP00000220822.7

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

GnomAD2 exomes AF: 0.241 AC: 31399 AN: 130496 AF XY: 0.233

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 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

African (AFR) AF: 0.150 AC: 1378 AN: 9208

American (AMR) AF: 0.396 AC: 10932 AN: 27628

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 2099 AN: 11398

East Asian (EAS) AF: 0.277 AC: 2765 AN: 9978

South Asian (SAS) AF: 0.248 AC: 14837 AN: 59790

European-Finnish (FIN) AF: 0.155 AC: 2003 AN: 12944

Middle Eastern (MID) AF: 0.226 AC: 281 AN: 1242

European-Non Finnish (NFE) AF: 0.179 AC: 30166 AN: 168196

Other (OTH) AF: 0.199 AC: 2966 AN: 14924

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

African (AFR) AF: 0.148 AC: 6132 AN: 41548

American (AMR) AF: 0.312 AC: 4771 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3462

East Asian (EAS) AF: 0.285 AC: 1470 AN: 5164

South Asian (SAS) AF: 0.246 AC: 1186 AN: 4828

European-Finnish (FIN) AF: 0.151 AC: 1598 AN: 10596

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12154 AN: 68010

Other (OTH) AF: 0.207 AC: 438 AN: 2112

Alfa AF: 0.179 Hom.: 699

Bravo AF: 0.200

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

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.19
DANN	Benign	0.52
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: rs1135715; hg19: chr8-75276959;