rs405567

Variant names:

• chr14-87933279-T-C
• rs405567
• NM_000153.4:c.*1453A>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.*1453A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 152,306 control chromosomes in the GnomAD database, including 19,176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19114 hom., cov: 32)
  • Exomes 𝑓: 0.53 (62 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.77
• Publications: 14 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, PanelApp Australia, Genomics England PanelApp, Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-87933279-T-C is Benign according to our data. Variant chr14-87933279-T-C is described in ClinVar as Benign. ClinVar VariationId is 314729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.597 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.*1453A>G		3_prime_UTR	Exon 17 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.*1453A>G		3_prime_UTR	Exon 16 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.*1453A>G		3_prime_UTR	Exon 17 of 17	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.*1453A>G		3_prime_UTR	Exon 17 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.*1453A>G		3_prime_UTR	Exon 16 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.*1453A>G		3_prime_UTR	Exon 17 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74744 AN: 151742 Hom.: 19084 Cov.: 32

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.485

GnomAD4 exome AF: 0.534 AC: 238 AN: 446 Hom.: 62 Cov.: 0 AF XY: 0.541 AC XY: 145 AN XY: 268

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.535 AC: 227 AN: 424

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.600 AC: 6 AN: 10

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.493 AC: 74827 AN: 151860 Hom.: 19114 Cov.: 32 AF XY: 0.488 AC XY: 36221 AN XY: 74230

African (AFR) AF: 0.603 AC: 24984 AN: 41414

American (AMR) AF: 0.396 AC: 6041 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 1702 AN: 3468

East Asian (EAS) AF: 0.187 AC: 962 AN: 5142

South Asian (SAS) AF: 0.425 AC: 2048 AN: 4816

European-Finnish (FIN) AF: 0.476 AC: 5031 AN: 10560

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.478 AC: 32439 AN: 67916

Other (OTH) AF: 0.490 AC: 1030 AN: 2104

Alfa AF: 0.483 Hom.: 30822

Bravo AF: 0.489

Asia WGS AF: 0.397 AC: 1381 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.17
DANN	Benign	0.71
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs405567; hg19: chr14-88399623; COSMIC: COSV54331851; COSMIC: COSV54331851;