14-87934009-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000153.4(GALC):c.*723G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,532,502 control chromosomes in the GnomAD database, including 171,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.49 ( 19135 hom., cov: 32)

Exomes 𝑓: 0.46 ( 152162 hom. )

Consequence

GALC
NM_000153.4 3_prime_UTR

Scores

Splicing: ADA: 0.00002946

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.34

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 14-87934009-C-T is Benign according to our data. Variant chr14-87934009-C-T is described in ClinVar as [Benign]. Clinvar id is 314736.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87934009-C-T is described in Lovd as [Benign].

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/exons	MANE	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.*723G>A		3_prime_UTR_variant	17/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.*723G>A	3_prime_UTR_variant	17/17	1	NM_000153.4	P1	P54803-1
GALC	ENST00000544807.6 linkuse as main transcript	c.1744-10G>A	splice_polypyrimidine_tract_variant, intron_variant		2			P54803-5
GALC	ENST00000555000.5 linkuse as main transcript	c.1279-10G>A	splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.493

AC:

74767

AN:

151772

Hom.:

19105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.603

Gnomad AMI

AF:

0.502

Gnomad AMR

AF:

0.397

Gnomad ASJ

AF:

0.491

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.477

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.478

Gnomad OTH

AF:

0.486

GnomAD3 exomes

AF:

0.419

AC:

54834

AN:

130728

Hom.:

12299

AF XY:

0.422

AC XY:

30113

AN XY:

71376

show subpopulations

Gnomad AFR exome

AF:

0.613

Gnomad AMR exome

AF:

0.323

Gnomad ASJ exome

AF:

0.487

Gnomad EAS exome

AF:

0.175

Gnomad SAS exome

AF:

0.417

Gnomad FIN exome

AF:

0.477

Gnomad NFE exome

AF:

0.477

Gnomad OTH exome

AF:

0.445

GnomAD4 exome

AF:

0.465

AC:

641532

AN:

1380612

Hom.:

152162

Cov.:

AF XY:

0.464

AC XY:

316034

AN XY:

681296

show subpopulations

Gnomad4 AFR exome

AF:

0.612

Gnomad4 AMR exome

AF:

0.334

Gnomad4 ASJ exome

AF:

0.484

Gnomad4 EAS exome

AF:

0.198

Gnomad4 SAS exome

AF:

0.417

Gnomad4 FIN exome

AF:

0.464

Gnomad4 NFE exome

AF:

0.477

Gnomad4 OTH exome

AF:

0.455

GnomAD4 genome

AF:

0.493

AC:

74850

AN:

151890

Hom.:

19135

Cov.:

AF XY:

0.488

AC XY:

36207

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.603

Gnomad4 AMR

AF:

0.396

Gnomad4 ASJ

AF:

0.491

Gnomad4 EAS

AF:

0.186

Gnomad4 SAS

AF:

0.425

Gnomad4 FIN

AF:

0.477

Gnomad4 NFE

AF:

0.478

Gnomad4 OTH

AF:

0.490

Alfa

AF:

0.462

Hom.:

7069

Bravo

AF:

0.489

Asia WGS

AF:

0.398

AC:

1382

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

-0.94

Cadd

Benign

0.032

Dann

Benign

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000029

dbscSNV1_RF

Benign

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over