rs10504576

Variant names:

• chr8-74354444-A-G
• rs10504576
• NM_018972.4:c.310+2978A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018972.4(GDAP1):​c.310+2978A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 152,100 control chromosomes in the GnomAD database, including 16,790 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (16790 hom., cov: 33)
• Consequence: GDAP1 NM_018972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	NM_018972.4	MANE Select	c.310+2978A>G		intron	N/A	NP_061845.2	Q8TB36-1
	GDAP1	NM_001362930.2		c.310+2978A>G		intron	N/A	NP_001349859.1	A0A6Q8PEZ4
	GDAP1	NM_001040875.4		c.106+2978A>G		intron	N/A	NP_001035808.1	Q8TB36-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	ENST00000220822.12	TSL:1 MANE Select	c.310+2978A>G		intron	N/A	ENSP00000220822.7	Q8TB36-1
	GDAP1	ENST00000434412.3	TSL:1	c.178+2978A>G		intron	N/A	ENSP00000417006.3	A0A7I2RYU0
	GDAP1	ENST00000675463.1		c.310+2978A>G		intron	N/A	ENSP00000502327.1	A0A6Q8PGS2

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71417 AN: 151982 Hom.: 16783 Cov.: 33

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.519

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.450

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.470 AC: 71457 AN: 152100 Hom.: 16790 Cov.: 33 AF XY: 0.471 AC XY: 34994 AN XY: 74346

African (AFR) AF: 0.452 AC: 18774 AN: 41492

American (AMR) AF: 0.412 AC: 6301 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1784 AN: 3470

East Asian (EAS) AF: 0.403 AC: 2086 AN: 5182

South Asian (SAS) AF: 0.519 AC: 2506 AN: 4826

European-Finnish (FIN) AF: 0.515 AC: 5449 AN: 10574

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32914 AN: 67950

Other (OTH) AF: 0.450 AC: 949 AN: 2110

Alfa AF: 0.483 Hom.: 9027

Bravo AF: 0.460

Asia WGS AF: 0.459 AC: 1590 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.81
PhyloP100		2.5
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: rs10504576; hg19: chr8-75266679; COSMIC: COSV55187151; COSMIC: COSV55187151;