8-74350409-GGGA-G

Variant names:

• chr8-74350409-GGGA-G
• rs201803887
• NM_018972.4:c.-51_-49delGAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_018972.4(GDAP1):​c.-51_-49delGAG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,134,114 control chromosomes in the GnomAD database, including 128 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (15 hom., cov: 34)
  • Exomes 𝑓: 0.0027 (113 hom.)
• Consequence: GDAP1 NM_018972.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.29
• Publications: 0 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

ENSG00000253596 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-74350409-GGGA-G is Benign according to our data. Variant chr8-74350409-GGGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 363718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.-51_-49delGAG		5_prime_UTR_variant	Exon 1 of 6	ENST00000220822.12	NP_061845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12	c.-51_-49delGAG		5_prime_UTR_variant	Exon 1 of 6	1	NM_018972.4	ENSP00000220822.7

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152222 Hom.: 15 Cov.: 34

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00869 AC: 2092 AN: 240826 AF XY: 0.00621

Gnomad AFR exome AF: 0.000640

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00367

GnomAD4 exome AF: 0.00270 AC: 2655 AN: 981774 Hom.: 113 AF XY: 0.00209 AC XY: 1064 AN XY: 508618

African (AFR) AF: 0.000448 AC: 11 AN: 24536

American (AMR) AF: 0.0583 AC: 2574 AN: 44116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23100

East Asian (EAS) AF: 0.00 AC: 0 AN: 37636

South Asian (SAS) AF: 0.00 AC: 0 AN: 76920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4378

European-Non Finnish (NFE) AF: 0.00000734 AC: 5 AN: 681080

Other (OTH) AF: 0.00145 AC: 65 AN: 44722

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152340 Hom.: 15 Cov.: 34 AF XY: 0.00297 AC XY: 221 AN XY: 74484

African (AFR) AF: 0.000337 AC: 14 AN: 41586

American (AMR) AF: 0.0269 AC: 412 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00208 Hom.: 1

Bravo AF: 0.00592

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth with Vocal Cord Paresis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth, Intermediate Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=294/6	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: rs201803887; hg19: chr8-75262644;