chr8-74350137-A-T

Variant names:

• chr8-74350137-A-T
• rs112493177
• ENST00000521872.2:n.180T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000521872.2(ENSG00000253596):​n.180T>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 376,594 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (2 hom.)
• Consequence: ENSG00000253596 ENST00000521872.2 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.366
• Publications: 0 publications found

Genes affected

ENSG00000253596 (HGNC:):

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-74350137-A-T is Benign according to our data. Variant chr8-74350137-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1216335.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000253596	ENST00000521872.2	n.180T>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
GDAP1	ENST00000675944.1	c.-316A>T		5_prime_UTR_variant	Exon 1 of 6			ENSP00000502673.1
GDAP1	ENST00000674806.1	c.-294A>T		5_prime_UTR_variant	Exon 1 of 6			ENSP00000502637.1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 711 AN: 151860 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00479

GnomAD4 exome AF: 0.000654 AC: 147 AN: 224620 Hom.: 2 AF XY: 0.000574 AC XY: 69 AN XY: 120230

African (AFR) AF: 0.0136 AC: 88 AN: 6460

American (AMR) AF: 0.00220 AC: 21 AN: 9536

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 5 AN: 6230

East Asian (EAS) AF: 0.00 AC: 0 AN: 10780

South Asian (SAS) AF: 0.0000547 AC: 2 AN: 36546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10226

Middle Eastern (MID) AF: 0.00120 AC: 1 AN: 830

European-Non Finnish (NFE) AF: 0.0000757 AC: 10 AN: 132042

Other (OTH) AF: 0.00167 AC: 20 AN: 11970

GnomAD4 genome AF: 0.00472 AC: 718 AN: 151974 Hom.: 6 Cov.: 32 AF XY: 0.00448 AC XY: 333 AN XY: 74286

African (AFR) AF: 0.0150 AC: 624 AN: 41466

American (AMR) AF: 0.00445 AC: 68 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67962

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00561

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 22, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.15
DANN	Benign	0.73
PhyloP100		-0.37
PromoterAI		0.0081	Neutral

Splicing

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

Other links and lift over

dbSNP: rs112493177; hg19: chr8-75262372;