14-87950751-G-GA

Variant names:

• chr14-87950751-G-GA
• rs11300320
• NM_000153.4:c.1162-4dupT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000153.4(GALC):​c.1162-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: GALC NM_000153.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.150
• Publications: 7 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_benign. The variant received -1 ACMG points.

• BP6: Variant 14-87950751-G-GA is Benign according to our data. Variant chr14-87950751-G-GA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 314750.

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.1162-4dupT		splice_region intron	N/A	NP_000144.2
	GALC	NM_001201401.2		c.1093-4dupT		splice_region intron	N/A	NP_001188330.1
	GALC	NM_001201402.2		c.1084-4dupT		splice_region intron	N/A	NP_001188331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.1162-4_1162-3insT		splice_region intron	N/A	ENSP00000261304.2
	GALC	ENST00000393568.8	TSL:2	c.1093-4_1093-3insT		splice_region intron	N/A	ENSP00000377198.4
	GALC	ENST00000393569.6	TSL:2	c.1084-4_1084-3insT		splice_region intron	N/A	ENSP00000377199.2

Frequencies

GnomAD3 genomes AF: 0.000241 AC: 36 AN: 149428 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000861

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.0000517 AC: 11 AN: 212618 AF XY: 0.0000173

Gnomad AFR exome AF: 0.000823

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 0.0000344 AC: 39 AN: 1134522 Hom.: 0 Cov.: 0 AF XY: 0.0000350 AC XY: 20 AN XY: 571880

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

African (AFR) AF: 0.00102 AC: 28 AN: 27468

American (AMR) AF: 0.00 AC: 0 AN: 38486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21758

East Asian (EAS) AF: 0.00 AC: 0 AN: 34008

South Asian (SAS) AF: 0.0000142 AC: 1 AN: 70208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4820

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 842368

Other (OTH) AF: 0.0000210 AC: 1 AN: 47668

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000501987), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000241 AC: 36 AN: 149540 Hom.: 0 Cov.: 0 AF XY: 0.000192 AC XY: 14 AN XY: 72838

African (AFR) AF: 0.000859 AC: 35 AN: 40764

American (AMR) AF: 0.00 AC: 0 AN: 14916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67296

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.00 Hom.: 6173

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Uncertain:1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.15

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: rs11300320; hg19: chr14-88417095;