rs45568734

Variant names:

• chr14-87982181-A-G
• rs45568734
• NM_000153.4:c.621+24T>C

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.621+24T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,356,700 control chromosomes in the GnomAD database, including 13,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1144 hom., cov: 32)
  • Exomes 𝑓: 0.14 (12260 hom.)
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.32
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-87982181-A-G is Benign according to our data. Variant chr14-87982181-A-G is described in ClinVar as Benign. ClinVar VariationId is 255379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.621+24T>C		intron_variant	Intron 6 of 16	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.621+24T>C		intron_variant	Intron 6 of 16	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17187 AN: 152068 Hom.: 1141 Cov.: 32

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0952

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.125 AC: 28975 AN: 232122 AF XY: 0.125

Gnomad AFR exome AF: 0.0354

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.00101

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.136 AC: 164109 AN: 1204514 Hom.: 12260 Cov.: 16 AF XY: 0.136 AC XY: 82910 AN XY: 610656

African (AFR) AF: 0.0334 AC: 949 AN: 28410

American (AMR) AF: 0.143 AC: 5839 AN: 40938

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2761 AN: 24096

East Asian (EAS) AF: 0.00117 AC: 44 AN: 37612

South Asian (SAS) AF: 0.0970 AC: 7392 AN: 76236

European-Finnish (FIN) AF: 0.162 AC: 8430 AN: 52142

Middle Eastern (MID) AF: 0.162 AC: 858 AN: 5290

European-Non Finnish (NFE) AF: 0.148 AC: 131332 AN: 888432

Other (OTH) AF: 0.127 AC: 6504 AN: 51358

GnomAD4 genome AF: 0.113 AC: 17196 AN: 152186 Hom.: 1144 Cov.: 32 AF XY: 0.113 AC XY: 8440 AN XY: 74400

African (AFR) AF: 0.0400 AC: 1662 AN: 41558

American (AMR) AF: 0.130 AC: 1993 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5182

South Asian (SAS) AF: 0.0951 AC: 459 AN: 4826

European-Finnish (FIN) AF: 0.156 AC: 1650 AN: 10570

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10611 AN: 67964

Other (OTH) AF: 0.108 AC: 229 AN: 2116

Alfa AF: 0.136 Hom.: 318

Bravo AF: 0.107

Asia WGS AF: 0.0550 AC: 190 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 26, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Galactosylceramide beta-galactosidase deficiency Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.62
PhyloP100		-1.3
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: rs45568734; hg19: chr14-88448525;