Variant 20-44263301-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_024034.6(GDAP1L1):c.619T>C(p.Tyr207His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,708 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GDAP1L1
NM_024034.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.41

Variant links:

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]

GDAP1L1 links:

GDAP1L1 (HGNC:):

GDAP1L1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDAP1L1	NM_024034.6 linkuse as main transcript	c.619T>C	p.Tyr207His	missense_variant	4/6	ENST00000342560.10	NP_076939.3	Q96MZ0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDAP1L1	ENST00000342560.10 linkuse as main transcript	c.619T>C	p.Tyr207His	missense_variant	4/6	1	NM_024034.6	ENSP00000341782.5		Q96MZ0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251458

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.619T>C (p.Y207H) alteration is located in exon 4 (coding exon 4) of the GDAP1L1 gene. This alteration results from a T to C substitution at nucleotide position 619, causing the tyrosine (Y) at amino acid position 207 to be replaced by a histidine (H). 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

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T;.;.

Eigen

Benign

0.043

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.0

.;M;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.9

.;D;.;N

REVEL

Pathogenic

0.72

Sift

Uncertain

0.020

.;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.0030

.;B;.;.

Vest4

0.66

MutPred

0.58

.;Loss of loop (P = 0.0112);.;.;

MVP

0.93

MPC

0.92

ClinPred

0.76

GERP RS

5.2

Varity_R

0.45

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over