8-74350551-T-C

Variant names:

• chr8-74350551-T-C
• rs555369956
• NM_018972.4:c.90T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001362929.2(GDAP1):​c.-93T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,609,066 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00037 (13 hom.)
• Consequence: GDAP1 NM_001362929.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.84
• 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

ENSG00000253596 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 8-74350551-T-C is Benign according to our data. Variant chr8-74350551-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 467775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00037 (539/1456718) while in subpopulation SAS AF = 0.00419 (361/86152). AF 95% confidence interval is 0.00383. There are 13 homozygotes in GnomAdExome4. There are 356 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001362929.2. 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.90T>C	p.His30His	synonymous	Exon 1 of 6	NP_061845.2	Q8TB36-1
	GDAP1	NM_001362929.2		c.-93T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001349858.1	B4DIH2
	GDAP1	NM_001362932.2		c.-45T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001349861.1	B4DIH2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	ENST00000220822.12	TSL:1 MANE Select	c.90T>C	p.His30His	synonymous	Exon 1 of 6	ENSP00000220822.7	Q8TB36-1
	GDAP1	ENST00000434412.3	TSL:1	c.90T>C	p.His30His	synonymous	Exon 1 of 7	ENSP00000417006.3	A0A7I2RYU0
	GDAP1	ENST00000675463.1		c.90T>C	p.His30His	synonymous	Exon 1 of 7	ENSP00000502327.1	A0A6Q8PGS2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000664 AC: 167 AN: 251362 AF XY: 0.000846

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000370 AC: 539 AN: 1456718 Hom.: 13 Cov.: 29 AF XY: 0.000491 AC XY: 356 AN XY: 725052

African (AFR) AF: 0.000120 AC: 4 AN: 33374

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00419 AC: 361 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.000144 AC: 160 AN: 1107362

Other (OTH) AF: 0.000150 AC: 9 AN: 60190

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152348 Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 12 AN XY: 74496

African (AFR) AF: 0.0000721 AC: 3 AN: 41602

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000576 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4A (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		1.8
PromoterAI		0.079	Neutral
Mutation Taster		=100/0	polymorphism

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: rs555369956; hg19: chr8-75262786;