rs387906955

Variant names:

• chr14-87993044-C-T
• rs387906955
• NM_000153.4:c.121G>A
• GALC p.Gly41Ser

Your query was ambiguous. Multiple possible variants found:

• chr14-87993044-C-T
• chr14-87993044-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP2 PP5 BP4

The NM_000153.4(GALC):​c.121G>A​(p.Gly41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.73
• Publications: 17 publications found

Genes affected

GALC (HGNC:4115): (galactosylceramidase) This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

GALC Gene-Disease associations (from GenCC):

• Krabbe disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Myriad Women's Health

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000153.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
• PP5: Variant 14-87993044-C-T is Pathogenic according to our data. Variant chr14-87993044-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30621.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26462346). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000153.4. 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
	GALC	NM_000153.4	MANE Select	c.121G>A	p.Gly41Ser	missense	Exon 1 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.121G>A	p.Gly41Ser	missense	Exon 1 of 16	NP_001188330.1	P54803-3
	GALC	NM_001424072.1		c.-150G>A		5_prime_UTR	Exon 1 of 18	NP_001411001.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.121G>A	p.Gly41Ser	missense	Exon 1 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.109G>A	p.Gly37Ser	missense	Exon 1 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.111G>A		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1404310 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 694604

African (AFR) AF: 0.00 AC: 0 AN: 30940

American (AMR) AF: 0.00 AC: 0 AN: 37708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24846

East Asian (EAS) AF: 0.00 AC: 0 AN: 36136

South Asian (SAS) AF: 0.00 AC: 0 AN: 80472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085944

Other (OTH) AF: 0.00 AC: 0 AN: 58102

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Galactosylceramide beta-galactosidase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.95	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.49	N
REVEL	Benign	0.23
Sift	Benign	0.40	T
Sift4G	Benign	0.69	T
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.039
gMVP		0.64
Mutation Taster		=27/73	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387906955;

hg19: chr14-88459388;