chr8-74350331-A-T

Variant names:

• chr8-74350331-A-T
• rs146798895
• ENST00000675944.1:c.-122A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000675944.1(GDAP1):​c.-122A>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00558 in 719,546 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (66 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (34 hom.)
• Consequence: GDAP1 ENST00000675944.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.92
• 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

ENSG00000253596 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 8-74350331-A-T is Benign according to our data. Variant chr8-74350331-A-T is described in ClinVar as [Benign]. Clinvar id is 1244430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.-131A>T		upstream_gene_variant		ENST00000220822.12	NP_061845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12	c.-131A>T		upstream_gene_variant		1	NM_018972.4	ENSP00000220822.7

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2664 AN: 151878 Hom.: 65 Cov.: 34

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00236 AC: 1340 AN: 567556 Hom.: 34 AF XY: 0.00199 AC XY: 609 AN XY: 306240

African (AFR) AF: 0.0591 AC: 954 AN: 16142

American (AMR) AF: 0.00461 AC: 164 AN: 35602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19722

East Asian (EAS) AF: 0.00 AC: 0 AN: 32536

South Asian (SAS) AF: 0.0000798 AC: 5 AN: 62652

European-Finnish (FIN) AF: 0.0000291 AC: 1 AN: 34306

Middle Eastern (MID) AF: 0.00164 AC: 4 AN: 2446

European-Non Finnish (NFE) AF: 0.000207 AC: 69 AN: 333092

Other (OTH) AF: 0.00460 AC: 143 AN: 31058

GnomAD4 genome AF: 0.0176 AC: 2677 AN: 151990 Hom.: 66 Cov.: 34 AF XY: 0.0169 AC XY: 1254 AN XY: 74290

African (AFR) AF: 0.0603 AC: 2501 AN: 41450

American (AMR) AF: 0.00824 AC: 126 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67970

Other (OTH) AF: 0.0152 AC: 32 AN: 2110

Alfa AF: 0.0131 Hom.: 2

Bravo AF: 0.0204

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Benign	0.91
PhyloP100		3.9
PromoterAI		-0.027	Neutral

Splicing

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

Other links and lift over

dbSNP: rs146798895; hg19: chr8-75262566;