14-87950751-GAA-GA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.1162-4delT 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (69014 hom., cov: 0)
  • Exomes 𝑓: 0.97 (530192 hom.)
• Consequence: GALC NM_000153.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:17
• 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: Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Myriad Women's Health

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 14-87950751-GA-G is Benign according to our data. Variant chr14-87950751-GA-G is described in ClinVar as Benign. ClinVar VariationId is 92493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.1162-4delT		splice_region intron	N/A	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1093-4delT		splice_region intron	N/A	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1084-4delT		splice_region intron	N/A	NP_001188331.1	P54803-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.1162-4delT		splice_region intron	N/A	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1123-4delT		splice_region intron	N/A	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1162-4delT		splice_region intron	N/A	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.959 AC: 143279 AN: 149400 Hom.: 68984 Cov.: 0

Gnomad AFR AF: 0.859

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.966

GnomAD2 exomes AF: 0.974 AC: 207143 AN: 212618 AF XY: 0.977

Gnomad AFR exome AF: 0.841

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.985

Gnomad EAS exome AF: 0.983

Gnomad FIN exome AF: 0.994

Gnomad NFE exome AF: 0.984

Gnomad OTH exome AF: 0.975

GnomAD4 exome AF: 0.967 AC: 1097368 AN: 1134968 Hom.: 530192 Cov.: 0 AF XY: 0.969 AC XY: 554172 AN XY: 572076

African (AFR) AF: 0.818 AC: 22461 AN: 27468

American (AMR) AF: 0.967 AC: 37240 AN: 38492

Ashkenazi Jewish (ASJ) AF: 0.976 AC: 21237 AN: 21760

East Asian (EAS) AF: 0.980 AC: 33322 AN: 34012

South Asian (SAS) AF: 0.972 AC: 68299 AN: 70232

European-Finnish (FIN) AF: 0.986 AC: 47063 AN: 47746

Middle Eastern (MID) AF: 0.975 AC: 4700 AN: 4820

European-Non Finnish (NFE) AF: 0.970 AC: 817173 AN: 842760

Other (OTH) AF: 0.962 AC: 45873 AN: 47678

GnomAD4 genome AF: 0.959 AC: 143367 AN: 149512 Hom.: 69014 Cov.: 0 AF XY: 0.961 AC XY: 69986 AN XY: 72826

African (AFR) AF: 0.858 AC: 34971 AN: 40738

American (AMR) AF: 0.985 AC: 14686 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3453 AN: 3460

East Asian (EAS) AF: 1.00 AC: 5073 AN: 5074

South Asian (SAS) AF: 0.999 AC: 4731 AN: 4734

European-Finnish (FIN) AF: 0.999 AC: 10007 AN: 10018

Middle Eastern (MID) AF: 0.997 AC: 289 AN: 290

European-Non Finnish (NFE) AF: 0.999 AC: 67239 AN: 67296

Other (OTH) AF: 0.966 AC: 2008 AN: 2078

Alfa AF: 0.953 Hom.: 6173

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Galactosylceramide beta-galactosidase deficiency (6)
-	-	6	not specified (6)
-	-	4	not provided (4)
1	-	-	Abnormal brain morphology (1)
-	-	1	GALC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.15
Mutation Taster		=98/2	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11300320;

hg19: chr14-88417095;

COSMIC: COSV54323120;

COSMIC: COSV54323120;