chr20-44258511-G-A

Variant names:

• chr20-44258511-G-A
• rs141872493
• NM_024034.6:c.451G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024034.6(GDAP1L1):​c.451G>A​(p.Ala151Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,568,454 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: GDAP1L1 NM_024034.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07793707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDAP1L1	NM_024034.6	c.451G>A	p.Ala151Thr	missense_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.451G>A	p.Ala151Thr	missense_variant	Exon 3 of 6	1	NM_024034.6	ENSP00000341782.5

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000291 AC: 52 AN: 178698 Hom.: 0 AF XY: 0.000407 AC XY: 39 AN XY: 95844

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000754

Gnomad SAS exome AF: 0.00138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.000419

GnomAD4 exome AF: 0.000268 AC: 380 AN: 1416164 Hom.: 1 Cov.: 32 AF XY: 0.000291 AC XY: 204 AN XY: 700364

Gnomad4 AFR exome AF: 0.000311

Gnomad4 AMR exome AF: 0.0000779

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00113

Gnomad4 FIN exome AF: 0.0000609

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.000136

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74456

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000150 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.451G>A (p.A151T) alteration is located in exon 3 (coding exon 3) of the GDAP1L1 gene. This alteration results from a G to A substitution at nucleotide position 451, causing the alanine (A) at amino acid position 151 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0096	T;T;.;.
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.011
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.078	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.57	.;N;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.12	.;T;.;.
Sift4G	Benign	0.078	T;T;T;T
Polyphen		0.043	.;B;.;.
Vest4		0.18
MVP		0.94
MPC		0.47
ClinPred		0.017	T
GERP RS		2.0
Varity_R		0.057
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs141872493; hg19: chr20-42887151;