14-87934009-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• Krabbe disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Genomics England PanelApp, Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 314736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000153.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.*723G>A		3_prime_UTR	Exon 17 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.*723G>A		3_prime_UTR	Exon 16 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.*723G>A		3_prime_UTR	Exon 17 of 17	NP_001188331.1	P54803-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.*723G>A		3_prime_UTR	Exon 17 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.*723G>A		3_prime_UTR	Exon 16 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.*723G>A		3_prime_UTR	Exon 17 of 17	ENSP00000620441.1

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

GnomAD2 exomes AF: 0.419 AC: 54834 AN: 130728 AF XY: 0.422

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 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

African (AFR) AF: 0.612 AC: 19251 AN: 31476

American (AMR) AF: 0.334 AC: 11909 AN: 35648

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 12148 AN: 25104

East Asian (EAS) AF: 0.198 AC: 7113 AN: 35838

South Asian (SAS) AF: 0.417 AC: 33009 AN: 79102

European-Finnish (FIN) AF: 0.464 AC: 15523 AN: 33442

Middle Eastern (MID) AF: 0.439 AC: 2492 AN: 5674

European-Non Finnish (NFE) AF: 0.477 AC: 513818 AN: 1076560

Other (OTH) AF: 0.455 AC: 26269 AN: 57768

GnomAD4 genome AF: 0.493 AC: 74850 AN: 151890 Hom.: 19135 Cov.: 32 AF XY: 0.488 AC XY: 36207 AN XY: 74192

African (AFR) AF: 0.603 AC: 25016 AN: 41458

American (AMR) AF: 0.396 AC: 6038 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 1701 AN: 3462

East Asian (EAS) AF: 0.186 AC: 955 AN: 5140

South Asian (SAS) AF: 0.425 AC: 2047 AN: 4816

European-Finnish (FIN) AF: 0.477 AC: 5024 AN: 10524

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32442 AN: 67932

Other (OTH) AF: 0.490 AC: 1035 AN: 2112

Alfa AF: 0.467 Hom.: 7822

Bravo AF: 0.489

Asia WGS AF: 0.398 AC: 1382 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.032
DANN	Benign	0.57
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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