1-117878138-A-T

Position:

• chr1-117878138-A-T

Variant summary

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

The NM_017686.4(GDAP2):​c.1317T>A​(p.Phe439Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GDAP2 NM_017686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

Genes affected

GDAP2 (HGNC:18010): (ganglioside induced differentiation associated protein 2) Predicted to act upstream of or within response to retinoic acid. Located in lysosomal membrane. Implicated in autosomal recessive spinocerebellar ataxia 27. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDAP2	NM_017686.4	c.1317T>A	p.Phe439Leu	missense_variant	13/14	ENST00000369443.10	NP_060156.1
GDAP2	NM_001135589.3	c.1317T>A	p.Phe439Leu	missense_variant	13/13		NP_001129061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDAP2	ENST00000369443.10	c.1317T>A	p.Phe439Leu	missense_variant	13/14	2	NM_017686.4	ENSP00000358451	P1
GDAP2	ENST00000369442.3	c.1317T>A	p.Phe439Leu	missense_variant	13/13	1		ENSP00000358450
GDAP2	ENST00000491626.5	n.323T>A		non_coding_transcript_exon_variant	5/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.1317T>A (p.F439L) alteration is located in exon 13 (coding exon 12) of the GDAP2 gene. This alteration results from a T to A substitution at nucleotide position 1317, causing the phenylalanine (F) at amino acid position 439 to be replaced by a leucine (L). 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	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.74	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.32	T;T
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.51		Loss of ubiquitination at K434 (P = 0.1612);Loss of ubiquitination at K434 (P = 0.1612);
MVP		0.73
MPC		0.38
ClinPred		0.86	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-118420760;