14-87934105-T-C

Position:

• chr14-87934105-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000153.4(GALC):​c.*627A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,505,686 control chromosomes in the GnomAD database, including 739,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.96 (70008 hom., cov: 34)
  • Exomes 𝑓: 0.99 (669188 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.73

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-87934105-T-C is Benign according to our data. Variant chr14-87934105-T-C is described in ClinVar as [Benign]. Clinvar id is 314738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.*627A>G		3_prime_UTR_variant	17/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.*627A>G		3_prime_UTR_variant	17/17	1	NM_000153.4	P1
GALC	ENST00000544807.6	c.1744-106A>G		intron_variant		2
GALC	ENST00000555000.5	c.1279-106A>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.957 AC: 145567 AN: 152072 Hom.: 69968 Cov.: 34

Gnomad AFR AF: 0.861

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.994

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.963

GnomAD4 exome AF: 0.994 AC: 1345526 AN: 1353496 Hom.: 669188 Cov.: 24 AF XY: 0.995 AC XY: 663312 AN XY: 666838

Gnomad4 AFR exome AF: 0.852

Gnomad4 AMR exome AF: 0.990

Gnomad4 ASJ exome AF: 0.998

Gnomad4 EAS exome AF: 0.955

Gnomad4 SAS exome AF: 0.997

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.985

GnomAD4 genome AF: 0.957 AC: 145667 AN: 152190 Hom.: 70008 Cov.: 34 AF XY: 0.958 AC XY: 71281 AN XY: 74398

Gnomad4 AFR AF: 0.861

Gnomad4 AMR AF: 0.984

Gnomad4 ASJ AF: 0.998

Gnomad4 EAS AF: 0.938

Gnomad4 SAS AF: 0.995

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.964

Alfa AF: 0.974 Hom.: 9138

Bravo AF: 0.950

Asia WGS AF: 0.960 AC: 3339 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.6
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs413750; hg19: chr14-88400449;