rs45572135

Variant names:

• chr14-87934023-T-G
• rs45572135
• NM_000153.4:c.*709A>C

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.*709A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0729 in 1,534,004 control chromosomes in the GnomAD database, including 4,644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (318 hom., cov: 33)
  • Exomes 𝑓: 0.075 (4326 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00700
• Publications: 7 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=-0.81).
• BP6: Variant 14-87934023-T-G is Benign according to our data. Variant chr14-87934023-T-G is described in ClinVar as Benign. ClinVar VariationId is 314737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0789 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.*709A>C		3_prime_UTR	Exon 17 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.*709A>C		3_prime_UTR	Exon 16 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.*709A>C		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.*709A>C		3_prime_UTR	Exon 17 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.*709A>C		3_prime_UTR	Exon 16 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.*709A>C		3_prime_UTR	Exon 17 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7911 AN: 152056 Hom.: 318 Cov.: 33

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.0799

Gnomad EAS AF: 0.000968

Gnomad SAS AF: 0.0489

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0807

Gnomad OTH AF: 0.0478

GnomAD2 exomes AF: 0.0571 AC: 7472 AN: 130826 AF XY: 0.0596

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.0771

Gnomad EAS exome AF: 0.000661

Gnomad FIN exome AF: 0.0339

Gnomad NFE exome AF: 0.0839

Gnomad OTH exome AF: 0.0770

GnomAD4 exome AF: 0.0752 AC: 103961 AN: 1381830 Hom.: 4326 Cov.: 32 AF XY: 0.0748 AC XY: 51021 AN XY: 681878

African (AFR) AF: 0.0120 AC: 377 AN: 31508

American (AMR) AF: 0.0402 AC: 1433 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.0738 AC: 1854 AN: 25106

East Asian (EAS) AF: 0.000390 AC: 14 AN: 35854

South Asian (SAS) AF: 0.0513 AC: 4064 AN: 79170

European-Finnish (FIN) AF: 0.0348 AC: 1165 AN: 33462

Middle Eastern (MID) AF: 0.0727 AC: 413 AN: 5678

European-Non Finnish (NFE) AF: 0.0841 AC: 90674 AN: 1077570

Other (OTH) AF: 0.0686 AC: 3967 AN: 57804

GnomAD4 genome AF: 0.0520 AC: 7910 AN: 152174 Hom.: 318 Cov.: 33 AF XY: 0.0489 AC XY: 3638 AN XY: 74386

African (AFR) AF: 0.0154 AC: 638 AN: 41546

American (AMR) AF: 0.0471 AC: 719 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0799 AC: 277 AN: 3468

East Asian (EAS) AF: 0.000970 AC: 5 AN: 5154

South Asian (SAS) AF: 0.0491 AC: 237 AN: 4826

European-Finnish (FIN) AF: 0.0277 AC: 294 AN: 10620

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0807 AC: 5486 AN: 67980

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0595 Hom.: 195

Bravo AF: 0.0531

Asia WGS AF: 0.0180 AC: 63 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	-0.81
CADD	Benign	7.1
DANN	Benign	0.57
PhyloP100		-0.0070
La Branchor		0.47
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs45572135; hg19: chr14-88400367;