20-44257219-G-C

Variant names:

• chr20-44257219-G-C
• rs767577909
• NM_024034.6:c.247G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024034.6(GDAP1L1):​c.247G>C​(p.Glu83Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E83K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GDAP1L1 NM_024034.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024034.6. 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
	GDAP1L1	NM_024034.6	MANE Select	c.247G>C	p.Glu83Gln	missense	Exon 2 of 6	NP_076939.3
	GDAP1L1	NM_001256737.2		c.247G>C	p.Glu83Gln	missense	Exon 2 of 6	NP_001243666.1	Q96MZ0-4
	GDAP1L1	NM_001256739.3		c.247G>C	p.Glu83Gln	missense	Exon 2 of 5	NP_001243668.1	B7Z1I3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1L1	ENST00000342560.10	TSL:1 MANE Select	c.247G>C	p.Glu83Gln	missense	Exon 2 of 6	ENSP00000341782.5	Q96MZ0-1
	GDAP1L1	ENST00000537864.5	TSL:2	c.247G>C	p.Glu83Gln	missense	Exon 2 of 6	ENSP00000440498.2	Q96MZ0-4
	GDAP1L1	ENST00000902255.1		c.247G>C	p.Glu83Gln	missense	Exon 2 of 6	ENSP00000572314.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726046

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 85846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111314

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.71		Gain of ubiquitination at K85 (P = 0.0725)
MVP		0.86
MPC		1.4
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.48
gMVP		0.54
Mutation Taster		=45/55	disease causing

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: rs767577909; hg19: chr20-42885859;