rs73345366

Variant names:

• chr8-74350276-G-A
• rs73345366
• ENST00000675944.1:c.-177G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000675944.1(GDAP1):​c.-177G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 648,720 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (7 hom., cov: 34)
  • Exomes 𝑓: 0.00062 (2 hom.)
• Consequence: GDAP1 ENST00000675944.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.164
• 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: 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

ENSG00000253596 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-74350276-G-A is Benign according to our data. Variant chr8-74350276-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1211968.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00446 (677/151814) while in subpopulation AFR AF = 0.0155 (643/41412). AF 95% confidence interval is 0.0145. There are 7 homozygotes in GnomAd4. There are 310 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675944.1. 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.-186G>A		upstream_gene	N/A	NP_061845.2	Q8TB36-1
	GDAP1	NM_001362930.2		c.-186G>A		upstream_gene	N/A	NP_001349859.1	A0A6Q8PEZ4
	GDAP1	NM_001040875.4		c.-260G>A		upstream_gene	N/A	NP_001035808.1	Q8TB36-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	ENST00000675944.1		c.-177G>A		5_prime_UTR	Exon 1 of 6	ENSP00000502673.1	Q8TB36-2
	GDAP1	ENST00000674806.1		c.-155G>A		5_prime_UTR	Exon 1 of 6	ENSP00000502637.1	B4DIH2
	GDAP1	ENST00000674612.1		c.-17-9861G>A		intron	N/A	ENSP00000501864.1	B4DIH2

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 672 AN: 151734 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

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: 0.0000736

Gnomad OTH AF: 0.00385

GnomAD4 exome AF: 0.000618 AC: 307 AN: 496906 Hom.: 2 AF XY: 0.000487 AC XY: 129 AN XY: 265090

African (AFR) AF: 0.0152 AC: 219 AN: 14424

American (AMR) AF: 0.00107 AC: 32 AN: 29932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16338

East Asian (EAS) AF: 0.00 AC: 0 AN: 31420

South Asian (SAS) AF: 0.0000936 AC: 5 AN: 53446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31374

Middle Eastern (MID) AF: 0.00138 AC: 3 AN: 2174

European-Non Finnish (NFE) AF: 0.0000380 AC: 11 AN: 289746

Other (OTH) AF: 0.00132 AC: 37 AN: 28052

GnomAD4 genome AF: 0.00446 AC: 677 AN: 151814 Hom.: 7 Cov.: 34 AF XY: 0.00418 AC XY: 310 AN XY: 74130

African (AFR) AF: 0.0155 AC: 643 AN: 41412

American (AMR) AF: 0.00137 AC: 21 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67970

Other (OTH) AF: 0.00382 AC: 8 AN: 2094

Alfa AF: 0.00401 Hom.: 0

Bravo AF: 0.00511

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.8
DANN	Benign	0.92
PhyloP100		0.16
PromoterAI		-0.072	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73345366; hg19: chr8-75262511;