8-74361972-A-G

Variant names:

• chr8-74361972-A-G
• rs1409470237
• NM_018972.4:c.573A>G
• GDAP1 p.Arg191Arg

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_018972.4(GDAP1):​c.573A>G​(p.Arg191Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R191R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GDAP1 NM_018972.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• 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: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease recessive intermediate A

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.

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.573A>G	p.Arg191Arg	synonymous	Exon 4 of 6	NP_061845.2	Q8TB36-1
	GDAP1	NM_001362930.2		c.399A>G	p.Arg133Arg	synonymous	Exon 3 of 5	NP_001349859.1	A0A6Q8PEZ4
	GDAP1	NM_001040875.4		c.369A>G	p.Arg123Arg	synonymous	Exon 4 of 6	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.573A>G	p.Arg191Arg	synonymous	Exon 4 of 6	ENSP00000220822.7	Q8TB36-1
	GDAP1	ENST00000434412.3	TSL:1	c.441A>G	p.Arg147Arg	synonymous	Exon 5 of 7	ENSP00000417006.3	A0A7I2RYU0
	GDAP1	ENST00000675463.1		c.573A>G	p.Arg191Arg	synonymous	Exon 4 of 7	ENSP00000502327.1	A0A6Q8PGS2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1419156 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 708792

African (AFR) AF: 0.00 AC: 0 AN: 32806

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 85498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074882

Other (OTH) AF: 0.00 AC: 0 AN: 59046

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.9
DANN	Benign	0.71
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1409470237;

hg19: chr8-75274207;