rs111887056

Positions:

chr14-87993104-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000153.4(GALC):c.61G>C(p.Ala21Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,586,544 control chromosomes in the GnomAD database, including 16,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1112 hom., cov: 33)

Exomes 𝑓: 0.14 ( 15567 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.562

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 (MetaRNN=0.0018750429).

BP6

Variant 14-87993104-C-G is Benign according to our data. Variant chr14-87993104-C-G is described in ClinVar as [Benign]. Clinvar id is 92508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87993104-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GALC	NM_000153.4 linkuse as main transcript	c.61G>C	p.Ala21Pro	missense_variant	1/17	ENST00000261304.7	NP_000144.2
GALC	NM_001201401.2 linkuse as main transcript	c.61G>C	p.Ala21Pro	missense_variant	1/16		NP_001188330.1
GALC	NM_001201402.2 linkuse as main transcript	c.117+279G>C		intron_variant			NP_001188331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.61G>C	p.Ala21Pro	missense_variant	1/17	1	NM_000153.4	ENSP00000261304	P1	P54803-1

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

17026

AN:

152156

Hom.:

1109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0395

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0947

Gnomad FIN

AF:

0.154

Gnomad MID

AF:

0.134

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.109

GnomAD3 exomes

AF:

0.115

AC:

21968

AN:

190848

Hom.:

1520

AF XY:

0.114

AC XY:

12010

AN XY:

105134

show subpopulations

Gnomad AFR exome

AF:

0.0329

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.000725

Gnomad SAS exome

AF:

0.0948

Gnomad FIN exome

AF:

0.148

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.142

AC:

203924

AN:

1434276

Hom.:

15567

Cov.:

AF XY:

0.141

AC XY:

100074

AN XY:

710896

show subpopulations

Gnomad4 AFR exome

AF:

0.0341

Gnomad4 AMR exome

AF:

0.139

Gnomad4 ASJ exome

AF:

0.117

Gnomad4 EAS exome

AF:

0.00124

Gnomad4 SAS exome

AF:

0.100

Gnomad4 FIN exome

AF:

0.158

Gnomad4 NFE exome

AF:

0.154

Gnomad4 OTH exome

AF:

0.131

GnomAD4 genome

AF:

0.112

AC:

17035

AN:

152268

Hom.:

1112

Cov.:

AF XY:

0.112

AC XY:

8361

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0396

Gnomad4 AMR

AF:

0.130

Gnomad4 ASJ

AF:

0.119

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.0946

Gnomad4 FIN

AF:

0.154

Gnomad4 NFE

AF:

0.154

Gnomad4 OTH

AF:

0.108

Alfa

AF:

0.140

Hom.:

554

Bravo

AF:

0.106

TwinsUK

AF:

0.139

AC:

517

ALSPAC

AF:

0.146

AC:

564

ESP6500AA

AF:

0.0366

AC:

109

ESP6500EA

AF:

0.115

AC:

777

ExAC

AF:

0.0887

AC:

10059

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -
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, 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:4

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

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

0.0069

P;P;P

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.020

N;N

REVEL

Uncertain

0.51

Sift

Benign

0.072

T;D

Sift4G

Benign

0.13

T;T

Polyphen

1.0

D;.

Vest4

0.17

MPC

0.66

ClinPred

0.033

GERP RS

3.2

Varity_R

0.14

gMVP

0.74

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

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