rs756414545

Variant names:

• chr20-44258497-G-A
• rs756414545
• NM_024034.6:c.437G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-44258497-G-A
• chr20-44258497-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024034.6(GDAP1L1):​c.437G>A​(p.Arg146Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,561,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: GDAP1L1 NM_024034.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.51
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

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.437G>A	p.Arg146Gln	missense	Exon 3 of 6	NP_076939.3
	GDAP1L1	NM_001256737.2		c.494G>A	p.Arg165Gln	missense	Exon 3 of 6	NP_001243666.1	Q96MZ0-4
	GDAP1L1	NM_001256740.2		c.437G>A	p.Arg146Gln	missense	Exon 3 of 4	NP_001243669.1	A0A087WWT8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1L1	ENST00000342560.10	TSL:1 MANE Select	c.437G>A	p.Arg146Gln	missense	Exon 3 of 6	ENSP00000341782.5	Q96MZ0-1
	GDAP1L1	ENST00000537864.5	TSL:2	c.494G>A	p.Arg165Gln	missense	Exon 3 of 6	ENSP00000440498.2	Q96MZ0-4
	GDAP1L1	ENST00000902255.1		c.437G>A	p.Arg146Gln	missense	Exon 3 of 6	ENSP00000572314.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000711 AC: 12 AN: 168758 AF XY: 0.0000554

Gnomad AFR exome AF: 0.000104

Gnomad AMR exome AF: 0.0000381

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000404

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000589

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000291 AC: 41 AN: 1409650 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 22 AN XY: 696554

African (AFR) AF: 0.0000313 AC: 1 AN: 31998

American (AMR) AF: 0.0000268 AC: 1 AN: 37302

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25228

East Asian (EAS) AF: 0.000192 AC: 7 AN: 36442

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 79970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48886

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5712

European-Non Finnish (NFE) AF: 0.0000249 AC: 27 AN: 1085688

Other (OTH) AF: 0.0000171 AC: 1 AN: 58424

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000253 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.9	L
PhyloP100		9.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.70		Loss of helix (P = 0.079)
MVP		0.98
MPC		1.5
ClinPred		0.27	T
GERP RS		5.4
Varity_R		0.37
gMVP		0.77
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756414545; hg19: chr20-42887137; COSMIC: COSV61158898;