chr14-87941390-G-C

Variant names:

• chr14-87941390-G-C
• rs448805
• NM_000153.4:c.1834+5C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.1834+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,563,728 control chromosomes in the GnomAD database, including 767,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (69652 hom., cov: 27)
  • Exomes 𝑓: 0.99 (698149 hom.)
• Consequence: GALC NM_000153.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002731
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.23
• Publications: 15 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: Laboratory for Molecular Medicine, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 14-87941390-G-C is Benign according to our data. Variant chr14-87941390-G-C is described in ClinVar as Benign. ClinVar VariationId is 92499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) 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.1834+5C>G		splice_region intron	N/A	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1765+5C>G		splice_region intron	N/A	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1756+5C>G		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.1834+5C>G		splice_region intron	N/A	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1795+5C>G		splice_region intron	N/A	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1768+5C>G		splice_region intron	N/A	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.957 AC: 144818 AN: 151256 Hom.: 69616 Cov.: 27

Gnomad AFR AF: 0.862

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.994

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.963

GnomAD2 exomes AF: 0.984 AC: 226807 AN: 230474 AF XY: 0.987

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 0.938

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.994 AC: 1403897 AN: 1412364 Hom.: 698149 Cov.: 27 AF XY: 0.995 AC XY: 700292 AN XY: 704036

African (AFR) AF: 0.852 AC: 27049 AN: 31732

American (AMR) AF: 0.991 AC: 41500 AN: 41884

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 25346 AN: 25390

East Asian (EAS) AF: 0.953 AC: 37572 AN: 39418

South Asian (SAS) AF: 0.997 AC: 80766 AN: 80982

European-Finnish (FIN) AF: 1.00 AC: 50579 AN: 50580

Middle Eastern (MID) AF: 0.991 AC: 5522 AN: 5574

European-Non Finnish (NFE) AF: 1.00 AC: 1077844 AN: 1078252

Other (OTH) AF: 0.986 AC: 57719 AN: 58552

GnomAD4 genome AF: 0.957 AC: 144909 AN: 151364 Hom.: 69652 Cov.: 27 AF XY: 0.958 AC XY: 70778 AN XY: 73864

African (AFR) AF: 0.861 AC: 35565 AN: 41284

American (AMR) AF: 0.984 AC: 14945 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3457 AN: 3464

East Asian (EAS) AF: 0.937 AC: 4780 AN: 5100

South Asian (SAS) AF: 0.995 AC: 4761 AN: 4786

European-Finnish (FIN) AF: 1.00 AC: 10422 AN: 10422

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67749 AN: 67808

Other (OTH) AF: 0.963 AC: 2025 AN: 2102

Alfa AF: 0.975 Hom.: 22763

Bravo AF: 0.951

Asia WGS AF: 0.959 AC: 3330 AN: 3472

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Galactosylceramide beta-galactosidase deficiency (5)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	GALC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.86
PhyloP100		3.2
Mutation Taster		=51/49	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.14
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: rs448805; hg19: chr14-88407734;