rs17687109

Variant names:

• chr14-87963346-A-G
• rs17687109
• ENST00000622264.4:c.1187T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 1P and 18B. PP2 BP4_Moderate BP6_Very_Strong BA1

The ENST00000622264.4(GALC):​c.1187T>C​(p.Leu396Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,595,282 control chromosomes in the GnomAD database, including 17,208 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1141 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16067 hom.)
• Consequence: GALC ENST00000622264.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0150
• Publications: 26 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: Laboratory for Molecular Medicine, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.94182 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
• BP4: Computational evidence support a benign effect (REVEL=0.091).
• BP6: Variant 14-87963346-A-G is Benign according to our data. Variant chr14-87963346-A-G is described in ClinVar as Benign. ClinVar VariationId is 255369.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: ENST00000622264.4. 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.1161+38T>C		intron	N/A	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1092+38T>C		intron	N/A	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1083+38T>C		intron	N/A	NP_001188331.1	P54803-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000622264.4	TSL:1	c.1187T>C	p.Leu396Pro	missense	Exon 10 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.1161+38T>C		intron	N/A	ENSP00000261304.2	P54803-1
	GALC	ENST00000474294.6	TSL:1	n.1189T>C		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17183 AN: 152032 Hom.: 1138 Cov.: 32

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0953

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.126 AC: 31394 AN: 248394 AF XY: 0.126

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.00201

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.143 AC: 207088 AN: 1443132 Hom.: 16067 Cov.: 27 AF XY: 0.142 AC XY: 102468 AN XY: 719364

African (AFR) AF: 0.0342 AC: 1134 AN: 33118

American (AMR) AF: 0.146 AC: 6515 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 3079 AN: 25996

East Asian (EAS) AF: 0.00164 AC: 65 AN: 39544

South Asian (SAS) AF: 0.102 AC: 8746 AN: 85930

European-Finnish (FIN) AF: 0.163 AC: 8683 AN: 53294

Middle Eastern (MID) AF: 0.162 AC: 926 AN: 5728

European-Non Finnish (NFE) AF: 0.155 AC: 170034 AN: 1095160

Other (OTH) AF: 0.132 AC: 7906 AN: 59720

GnomAD4 genome AF: 0.113 AC: 17192 AN: 152150 Hom.: 1141 Cov.: 32 AF XY: 0.113 AC XY: 8434 AN XY: 74382

African (AFR) AF: 0.0400 AC: 1661 AN: 41544

American (AMR) AF: 0.130 AC: 1985 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5180

South Asian (SAS) AF: 0.0951 AC: 459 AN: 4824

European-Finnish (FIN) AF: 0.156 AC: 1647 AN: 10578

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10620 AN: 67972

Other (OTH) AF: 0.108 AC: 229 AN: 2112

Alfa AF: 0.134 Hom.: 2912

Bravo AF: 0.107

Asia WGS AF: 0.0550 AC: 192 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		0.015
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: rs17687109; hg19: chr14-88429690; COSMIC: COSV54324625;