rs759110815

Variant names:

• chr14-87992986-G-A
• rs759110815
• NM_000153.4:c.179C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_000153.4(GALC):​c.179C>T​(p.Ala60Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000363 in 1,376,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A60A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 2.98
• Publications: 2 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: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 14-87992986-G-A is Pathogenic according to our data. Variant chr14-87992986-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 551142.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.179C>T	p.Ala60Val	missense	Exon 1 of 17	NP_000144.2
	GALC	NM_001201401.2		c.179C>T	p.Ala60Val	missense	Exon 1 of 16	NP_001188330.1
	GALC	NR_187582.1		n.197C>T		non_coding_transcript_exon	Exon 1 of 16

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.179C>T	p.Ala60Val	missense	Exon 1 of 17	ENSP00000261304.2
	GALC	ENST00000622264.4	TSL:1	c.167C>T	p.Ala56Val	missense	Exon 1 of 10	ENSP00000480649.1
	GALC	ENST00000474294.6	TSL:1	n.169C>T		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000225 AC: 3 AN: 133480 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000396

Gnomad ASJ exome AF: 0.000135

Gnomad EAS 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: 0.00000363 AC: 5 AN: 1376222 Hom.: 0 Cov.: 33 AF XY: 0.00000294 AC XY: 2 AN XY: 680934

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28148

American (AMR) AF: 0.0000273 AC: 1 AN: 36684

Ashkenazi Jewish (ASJ) AF: 0.0000413 AC: 1 AN: 24208

East Asian (EAS) AF: 0.00 AC: 0 AN: 32854

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 77864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4034

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078906

Other (OTH) AF: 0.00 AC: 0 AN: 56986

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0256219), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000958 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Uncertain:2

Dec 29, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 16, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

not provided Pathogenic:1

Jun 09, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM5, PS3_moderate

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.91	P
Vest4		0.87
MutPred		0.70		Gain of catalytic residue at G65 (P = 0)
MVP		0.95
MPC		0.23
ClinPred		0.91	D
GERP RS		2.3
PromoterAI		0.024	Neutral
Varity_R		0.29
gMVP		0.91
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs759110815; hg19: chr14-88459330;