NM_000153.4:c.*723G>A

Variant names:

• chr14-87934009-C-T
• rs412915
• NM_000153.4:c.*723G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.34

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=-0.94).
• 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.*723G>A		3_prime_UTR_variant	Exon 17 of 17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304	c.*723G>A		3_prime_UTR_variant	Exon 17 of 17	1	NM_000153.4	ENSP00000261304.2
GALC	ENST00000544807.6	c.1744-10G>A		intron_variant	Intron 16 of 16	2		ENSP00000437513.2
GALC	ENST00000555000.5	n.1279-10G>A		intron_variant	Intron 11 of 13	2		ENSP00000450472.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74767 AN: 151772 Hom.: 19105 Cov.: 32

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

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.: 35 AF XY: 0.464 AC XY: 316034 AN XY: 681296

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.: 32 AF XY: 0.488 AC XY: 36207 AN XY: 74192

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Other links and lift over

dbSNP: rs412915; hg19: chr14-88400353; COSMIC: COSV54325779; COSMIC: COSV54325779;