rs115018138

Positions:

• chr14-87941441-G-A
• chr14-87941441-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000153.4(GALC):​c.1788C>T​(p.Phe596=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00115 in 1,607,910 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (6 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.01

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 14-87941441-G-A is Benign according to our data. Variant chr14-87941441-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 456715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87941441-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00611 (918/150332) while in subpopulation AFR AF= 0.0214 (879/41038). AF 95% confidence interval is 0.0202. There are 11 homozygotes in gnomad4. There are 438 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.1788C>T	p.Phe596=	synonymous_variant	15/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.1788C>T	p.Phe596=	synonymous_variant	15/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 915 AN: 150276 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

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: 0.00338

GnomAD3 exomes AF: 0.00159 AC: 395 AN: 248612 Hom.: 5 AF XY: 0.00130 AC XY: 176 AN XY: 134900

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000799

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000637 AC: 929 AN: 1457578 Hom.: 6 Cov.: 33 AF XY: 0.000560 AC XY: 406 AN XY: 725324

Gnomad4 AFR exome AF: 0.0232

Gnomad4 AMR exome AF: 0.000806

Gnomad4 ASJ exome AF: 0.000461

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000244

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00611 AC: 918 AN: 150332 Hom.: 11 Cov.: 32 AF XY: 0.00598 AC XY: 438 AN XY: 73228

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.00159

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: 0.00336

Alfa AF: 0.00208 Hom.: 2

Bravo AF: 0.00696

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

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, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs115018138; hg19: chr14-88407785;