rs56194647

Variant names:

• chr14-87986534-A-G
• rs56194647
• NM_000153.4:c.397T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000153.4(GALC):​c.397T>C​(p.Leu133Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,613,542 control chromosomes in the GnomAD database, including 280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (153 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (127 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.75
• Publications: 5 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 14-87986534-A-G is Benign according to our data. Variant chr14-87986534-A-G is described in ClinVar as Benign. ClinVar VariationId is 255376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0797 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.397T>C	p.Leu133Leu	synonymous	Exon 4 of 17	NP_000144.2
	GALC	NM_001424076.1		c.-271T>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 18	NP_001411005.1
	GALC	NM_001424077.1		c.-271T>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 18	NP_001411006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.397T>C	p.Leu133Leu	synonymous	Exon 4 of 17	ENSP00000261304.2
	GALC	ENST00000622264.4	TSL:1	c.385T>C	p.Leu129Leu	synonymous	Exon 4 of 10	ENSP00000480649.1
	GALC	ENST00000474294.6	TSL:1	n.387T>C		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3593 AN: 152118 Hom.: 154 Cov.: 32

Gnomad AFR AF: 0.0819

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.00635 AC: 1583 AN: 249412 AF XY: 0.00464

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000442

Gnomad OTH exome AF: 0.00479

GnomAD4 exome AF: 0.00263 AC: 3841 AN: 1461306 Hom.: 127 Cov.: 30 AF XY: 0.00224 AC XY: 1629 AN XY: 727000

African (AFR) AF: 0.0860 AC: 2875 AN: 33442

American (AMR) AF: 0.00552 AC: 247 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5764

European-Non Finnish (NFE) AF: 0.000265 AC: 295 AN: 1111532

Other (OTH) AF: 0.00558 AC: 337 AN: 60376

GnomAD4 genome AF: 0.0237 AC: 3608 AN: 152236 Hom.: 153 Cov.: 32 AF XY: 0.0221 AC XY: 1647 AN XY: 74446

African (AFR) AF: 0.0820 AC: 3404 AN: 41500

American (AMR) AF: 0.00830 AC: 127 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68014

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0126 Hom.: 53

Bravo AF: 0.0269

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Galactosylceramide beta-galactosidase deficiency (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	5.9
DANN	Benign	0.75
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	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: rs56194647; hg19: chr14-88452878;