14-87933606-C-T

Variant names:

• chr14-87933606-C-T
• rs1042035
• NM_000153.4:c.*1126G>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.*1126G>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 0.115 in 178,520 control chromosomes in the GnomAD database, including 1,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1141 hom., cov: 33)
  • Exomes 𝑓: 0.14 (304 hom.)
• Consequence: GALC NM_000153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16
• Publications: 13 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=-0.87).
• BP6: Variant 14-87933606-C-T is Benign according to our data. Variant chr14-87933606-C-T is described in ClinVar as Benign. ClinVar VariationId is 314733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 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.*1126G>A		3_prime_UTR	Exon 17 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.*1126G>A		3_prime_UTR	Exon 16 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.*1126G>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.*1126G>A		3_prime_UTR	Exon 17 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.*1126G>A		3_prime_UTR	Exon 16 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.*1126G>A		3_prime_UTR	Exon 17 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16717 AN: 151996 Hom.: 1139 Cov.: 33

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0955

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.142 AC: 3743 AN: 26404 Hom.: 304 Cov.: 0 AF XY: 0.147 AC XY: 1950 AN XY: 13270

African (AFR) AF: 0.0374 AC: 41 AN: 1096

American (AMR) AF: 0.135 AC: 141 AN: 1042

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 144 AN: 1118

East Asian (EAS) AF: 0.00583 AC: 12 AN: 2058

South Asian (SAS) AF: 0.125 AC: 48 AN: 384

European-Finnish (FIN) AF: 0.166 AC: 157 AN: 948

Middle Eastern (MID) AF: 0.172 AC: 23 AN: 134

European-Non Finnish (NFE) AF: 0.166 AC: 2961 AN: 17822

Other (OTH) AF: 0.120 AC: 216 AN: 1802

GnomAD4 genome AF: 0.110 AC: 16717 AN: 152116 Hom.: 1141 Cov.: 33 AF XY: 0.110 AC XY: 8158 AN XY: 74342

African (AFR) AF: 0.0293 AC: 1218 AN: 41544

American (AMR) AF: 0.127 AC: 1938 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5176

South Asian (SAS) AF: 0.0949 AC: 458 AN: 4824

European-Finnish (FIN) AF: 0.156 AC: 1645 AN: 10568

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10641 AN: 67962

Other (OTH) AF: 0.108 AC: 228 AN: 2116

Alfa AF: 0.145 Hom.: 393

Bravo AF: 0.102

Asia WGS AF: 0.0560 AC: 195 AN: 3470

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	-0.87
CADD	Benign	1.2
DANN	Benign	0.65
PhyloP100		-1.2
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: rs1042035; hg19: chr14-88399950;