rs432946

Variant names:

• chr14-87934106-G-A
• rs432946
• NM_000153.4:c.*626C>T

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.*626C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,496,608 control chromosomes in the GnomAD database, including 166,121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19129 hom., cov: 34)
  • Exomes 𝑓: 0.46 (146992 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.12
• Publications: 9 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=-0.8).
• BP6: Variant 14-87934106-G-A is Benign according to our data. Variant chr14-87934106-G-A is described in ClinVar as Benign. ClinVar VariationId is 314739.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.*626C>T		3_prime_UTR	Exon 17 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.*626C>T		3_prime_UTR	Exon 16 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.*626C>T		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.*626C>T		3_prime_UTR	Exon 17 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.*626C>T		3_prime_UTR	Exon 16 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.*626C>T		3_prime_UTR	Exon 17 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74806 AN: 151854 Hom.: 19099 Cov.: 34

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.487

GnomAD4 exome AF: 0.463 AC: 622699 AN: 1344636 Hom.: 146992 Cov.: 24 AF XY: 0.462 AC XY: 305847 AN XY: 661946

African (AFR) AF: 0.609 AC: 18519 AN: 30418

American (AMR) AF: 0.328 AC: 11117 AN: 33874

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 11016 AN: 23272

East Asian (EAS) AF: 0.198 AC: 7021 AN: 35488

South Asian (SAS) AF: 0.409 AC: 30426 AN: 74430

European-Finnish (FIN) AF: 0.459 AC: 14795 AN: 32264

Middle Eastern (MID) AF: 0.433 AC: 2174 AN: 5022

European-Non Finnish (NFE) AF: 0.477 AC: 502185 AN: 1053714

Other (OTH) AF: 0.453 AC: 25446 AN: 56154

GnomAD4 genome AF: 0.493 AC: 74889 AN: 151972 Hom.: 19129 Cov.: 34 AF XY: 0.488 AC XY: 36245 AN XY: 74250

African (AFR) AF: 0.603 AC: 24992 AN: 41450

American (AMR) AF: 0.396 AC: 6044 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1703 AN: 3472

East Asian (EAS) AF: 0.187 AC: 965 AN: 5156

South Asian (SAS) AF: 0.424 AC: 2047 AN: 4826

European-Finnish (FIN) AF: 0.479 AC: 5054 AN: 10548

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32457 AN: 67960

Other (OTH) AF: 0.491 AC: 1036 AN: 2110

Alfa AF: 0.498 Hom.: 4693

Bravo AF: 0.489

Asia WGS AF: 0.398 AC: 1382 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	-0.80
CADD	Benign	8.3
DANN	Benign	0.47
PhyloP100		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: rs432946; hg19: chr14-88400450;