20-44258605-G-T

Variant names:

• chr20-44258605-G-T
• NM_024034.6:c.545G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024034.6(GDAP1L1):​c.545G>T​(p.Arg182Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GDAP1L1 NM_024034.6 missense, splice_region
• Scores: Splicing: ADA: 0.9974
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.56

Genes affected

GDAP1L1 (HGNC:4213): (ganglioside induced differentiation associated protein 1 like 1) The ganglioside GD3 synthase causes cell differentiation with neurite sprouting when transfected into the mouse neuroblastoma cell line Neuro2a. After differentiation, the expression of several genes is upregulated, including one that encodes a protein termed ganglioside-induced differentiation-associated protein 1 (Gdap1). A similar gene was found in humans, and mutations in the human gene are associated with Charcot-Marie-Tooth type 4A disease. The protein encoded by this gene is similar in sequence to the human GDAP1 protein. Several transcript variants encoding different isoforms, as well as a noncoding transcript variant, have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDAP1L1	NM_024034.6	c.545G>T	p.Arg182Leu	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000342560.10	NP_076939.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDAP1L1	ENST00000342560.10	c.545G>T	p.Arg182Leu	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_024034.6	ENSP00000341782.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445238 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717348

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T;T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	.;L;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	.;N;.;.
REVEL	Pathogenic	0.89
Sift	Benign	0.071	.;T;.;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.99	.;D;.;.
Vest4		0.89
MutPred		0.69		.;Loss of catalytic residue at R182 (P = 0.0151);.;Loss of catalytic residue at R182 (P = 0.0151);
MVP		0.97
MPC		1.5
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.29
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-42887245;