rs191767015

Positions:

• chr14-87992960-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000153.4(GALC):​c.195+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,512,872 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (2 hom.)
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.90

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-87992960-T-C is Benign according to our data. Variant chr14-87992960-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 456716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87992960-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00604 (920/152230) while in subpopulation AFR AF= 0.0212 (883/41562). AF 95% confidence interval is 0.0201. There are 13 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4	c.195+10A>G		intron_variant		ENST00000261304.7	NP_000144.2
GALC	NM_001201401.2	c.195+10A>G		intron_variant			NP_001188330.1
GALC	NM_001201402.2	c.117+423A>G		intron_variant			NP_001188331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.195+10A>G		intron_variant		1	NM_000153.4	ENSP00000261304	P1

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 917 AN: 152122 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000392 AC: 46 AN: 117494 Hom.: 0 AF XY: 0.000227 AC XY: 15 AN XY: 65998

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.000341

Gnomad ASJ exome AF: 0.000559

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000634

Gnomad OTH exome AF: 0.000299

GnomAD4 exome AF: 0.000575 AC: 783 AN: 1360642 Hom.: 2 Cov.: 33 AF XY: 0.000500 AC XY: 336 AN XY: 672246

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.000460

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000260

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000233

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00604 AC: 920 AN: 152230 Hom.: 13 Cov.: 33 AF XY: 0.00587 AC XY: 437 AN XY: 74430

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00327 Hom.: 1

Bravo AF: 0.00699

Asia WGS AF: 0.00116 AC: 4 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 04, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.35

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

Other links and lift over

dbSNP: rs191767015; hg19: chr14-88459304;