8-74363052-A-T

Variant names:

• chr8-74363052-A-T
• rs181157785
• NM_018972.4:c.693A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_018972.4(GDAP1):​c.693A>T​(p.Pro231Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,312,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: GDAP1 NM_018972.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.5533
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 2.76
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 8-74363052-A-T is Benign according to our data. Variant chr8-74363052-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379724.
• BP7: Synonymous conserved (PhyloP=2.76 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	NM_018972.4	MANE Select	c.693A>T	p.Pro231Pro	splice_region synonymous	Exon 5 of 6	NP_061845.2
	GDAP1	NM_001362930.2		c.519A>T	p.Pro173Pro	splice_region synonymous	Exon 4 of 5	NP_001349859.1
	GDAP1	NM_001040875.4		c.489A>T	p.Pro163Pro	splice_region synonymous	Exon 5 of 6	NP_001035808.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	ENST00000220822.12	TSL:1 MANE Select	c.693A>T	p.Pro231Pro	splice_region synonymous	Exon 5 of 6	ENSP00000220822.7
	GDAP1	ENST00000434412.3	TSL:1	c.561A>T	p.Pro187Pro	splice_region synonymous	Exon 6 of 7	ENSP00000417006.3
	GDAP1	ENST00000675463.1		c.693A>T	p.Pro231Pro	splice_region synonymous	Exon 5 of 7	ENSP00000502327.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152028 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000840 AC: 21 AN: 250146 AF XY: 0.0000959

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 168 AN: 1160500 Hom.: 0 Cov.: 17 AF XY: 0.000122 AC XY: 72 AN XY: 592220

African (AFR) AF: 0.00 AC: 0 AN: 27778

American (AMR) AF: 0.0000226 AC: 1 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24262

East Asian (EAS) AF: 0.00 AC: 0 AN: 38316

South Asian (SAS) AF: 0.00 AC: 0 AN: 80184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5174

European-Non Finnish (NFE) AF: 0.000196 AC: 164 AN: 836836

Other (OTH) AF: 0.0000595 AC: 3 AN: 50426

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152146 Hom.: 0 Cov.: 29 AF XY: 0.0000807 AC XY: 6 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41520

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease (1)
-	1	-	Charcot-Marie-Tooth disease recessive intermediate A (1)
-	1	-	Charcot-Marie-Tooth disease type 4A (1)
-	1	-	Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.72
PhyloP100		2.8
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.55
dbscSNV1_RF	Benign	0.53
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: rs181157785; hg19: chr8-75275287; COSMIC: COSV105875324; COSMIC: COSV105875324;