rs366615

Variant names:

• chr14-87945493-G-A
• rs366615
• NM_000153.4:c.1670+60C>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.1670+60C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,238,394 control chromosomes in the GnomAD database, including 136,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19102 hom., cov: 32)
  • Exomes 𝑓: 0.46 (117643 hom.)
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0990
• Publications: 10 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=-0.8).
• BP6: Variant 14-87945493-G-A is Benign according to our data. Variant chr14-87945493-G-A is described in ClinVar as Benign. ClinVar VariationId is 1177549.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.1670+60C>T		intron_variant	Intron 14 of 16	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.1670+60C>T		intron_variant	Intron 14 of 16	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74684 AN: 151694 Hom.: 19072 Cov.: 32

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.486

GnomAD4 exome AF: 0.459 AC: 498892 AN: 1086582 Hom.: 117643 AF XY: 0.458 AC XY: 256016 AN XY: 558468

African (AFR) AF: 0.611 AC: 15906 AN: 26032

American (AMR) AF: 0.325 AC: 14320 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 11475 AN: 23718

East Asian (EAS) AF: 0.195 AC: 7401 AN: 37926

South Asian (SAS) AF: 0.417 AC: 32697 AN: 78402

European-Finnish (FIN) AF: 0.470 AC: 24933 AN: 53100

Middle Eastern (MID) AF: 0.439 AC: 2166 AN: 4936

European-Non Finnish (NFE) AF: 0.478 AC: 368173 AN: 770540

Other (OTH) AF: 0.455 AC: 21821 AN: 47912

GnomAD4 genome AF: 0.492 AC: 74767 AN: 151812 Hom.: 19102 Cov.: 32 AF XY: 0.487 AC XY: 36159 AN XY: 74176

African (AFR) AF: 0.603 AC: 24990 AN: 41446

American (AMR) AF: 0.396 AC: 6025 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 1701 AN: 3466

East Asian (EAS) AF: 0.185 AC: 951 AN: 5128

South Asian (SAS) AF: 0.424 AC: 2042 AN: 4816

European-Finnish (FIN) AF: 0.475 AC: 5005 AN: 10534

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

European-Non Finnish (NFE) AF: 0.478 AC: 32428 AN: 67890

Other (OTH) AF: 0.490 AC: 1033 AN: 2108

Alfa AF: 0.333 Hom.: 1008

Bravo AF: 0.489

Asia WGS AF: 0.398 AC: 1385 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

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	-0.80
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		-0.099
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: rs366615; hg19: chr14-88411837; COSMIC: COSV54328654;