rs1135715

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-74364724-A-G
• chr8-74364724-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.*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.

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.*357A>G		3_prime_UTR	Exon 6 of 6	NP_061845.2	Q8TB36-1
	GDAP1	NM_001362930.2		c.*357A>G		3_prime_UTR	Exon 5 of 5	NP_001349859.1	A0A6Q8PEZ4
	GDAP1	NM_001040875.4		c.*357A>G		3_prime_UTR	Exon 6 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.*357A>G		3_prime_UTR	Exon 6 of 6	ENSP00000220822.7	Q8TB36-1
	GDAP1	ENST00000434412.3	TSL:1	c.*357A>G		3_prime_UTR	Exon 7 of 7	ENSP00000417006.3	A0A7I2RYU0
	GDAP1	ENST00000675463.1		c.*357A>G		3_prime_UTR	Exon 7 of 7	ENSP00000502327.1	A0A6Q8PGS2

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease recessive intermediate A (1)
-	-	1	Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;