rs11552556

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000153.4(GALC):c.330C>T(p.Asp110=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.04 in 1,602,176 control chromosomes in the GnomAD database, including 1,549 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 0.031 ( 126 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1423 hom. )

Consequence

GALC
NM_000153.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00003664

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.75

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 14-87986601-G-A is Benign according to our data. Variant chr14-87986601-G-A is described in ClinVar as [Benign]. Clinvar id is 92502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87986601-G-A is described in Lovd as [Benign]. Variant chr14-87986601-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.031 (4712/152096) while in subpopulation NFE AF= 0.0465 (3162/67992). AF 95% confidence interval is 0.0452. There are 126 homozygotes in gnomad4. There are 2282 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 126 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.330C>T	p.Asp110=	splice_region_variant, synonymous_variant	4/17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.330C>T	p.Asp110=	splice_region_variant, synonymous_variant	4/17	1	NM_000153.4	ENSP00000261304	P1	P54803-1

Frequencies

GnomAD3 genomes

AF:

0.0310

AC:

4711

AN:

151978

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00846

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0490

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.0501

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.0345

GnomAD3 exomes

AF:

0.0331

AC:

8216

AN:

248540

Hom.:

190

AF XY:

0.0340

AC XY:

4589

AN XY:

134832

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0493

Gnomad EAS exome

AF:

0.00117

Gnomad SAS exome

AF:

0.0217

Gnomad FIN exome

AF:

0.0565

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0309

GnomAD4 exome

AF:

0.0410

AC:

59415

AN:

1450080

Hom.:

1423

Cov.:

AF XY:

0.0408

AC XY:

29482

AN XY:

722150

show subpopulations

Gnomad4 AFR exome

AF:

0.00518

Gnomad4 AMR exome

AF:

0.0170

Gnomad4 ASJ exome

AF:

0.0500

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0213

Gnomad4 FIN exome

AF:

0.0528

Gnomad4 NFE exome

AF:

0.0458

Gnomad4 OTH exome

AF:

0.0334

GnomAD4 genome

AF:

0.0310

AC:

4712

AN:

152096

Hom.:

126

Cov.:

AF XY:

0.0307

AC XY:

2282

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00844

Gnomad4 AMR

AF:

0.0183

Gnomad4 ASJ

AF:

0.0490

Gnomad4 EAS

AF:

0.000775

Gnomad4 SAS

AF:

0.0191

Gnomad4 FIN

AF:

0.0501

Gnomad4 NFE

AF:

0.0465

Gnomad4 OTH

AF:

0.0337

Alfa

AF:

0.0413

Hom.:

210

Bravo

AF:

0.0284

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0465

EpiControl

AF:

0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 03, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000037

dbscSNV1_RF

Benign

0.11

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over