14-87947814-G-C

Variant names:

• chr14-87947814-G-C
• rs34134328
• NM_000153.4:c.1403C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000153.4(GALC):​c.1403C>G​(p.Thr468Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000845 in 1,612,742 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 7.53
• Publications: 6 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 -10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000153.4
• 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: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0118046105).
• BP6: Variant 14-87947814-G-C is Benign according to our data. Variant chr14-87947814-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92495.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00446 (678/152168) while in subpopulation AFR AF = 0.0155 (643/41546). AF 95% confidence interval is 0.0145. There are 4 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.1403C>G	p.Thr468Ser	missense	Exon 13 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1334C>G	p.Thr445Ser	missense	Exon 12 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1325C>G	p.Thr442Ser	missense	Exon 13 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.1403C>G	p.Thr468Ser	missense	Exon 13 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1364C>G	p.Thr455Ser	missense	Exon 12 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1337C>G	p.Thr446Ser	missense	Exon 13 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.00439 AC: 667 AN: 152050 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00110 AC: 273 AN: 248876 AF XY: 0.000763

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.000494

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000469 AC: 685 AN: 1460574 Hom.: 2 Cov.: 31 AF XY: 0.000398 AC XY: 289 AN XY: 726648

African (AFR) AF: 0.0167 AC: 559 AN: 33392

American (AMR) AF: 0.000672 AC: 30 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111110

Other (OTH) AF: 0.00143 AC: 86 AN: 60302

GnomAD4 genome AF: 0.00446 AC: 678 AN: 152168 Hom.: 4 Cov.: 32 AF XY: 0.00444 AC XY: 330 AN XY: 74404

African (AFR) AF: 0.0155 AC: 643 AN: 41546

American (AMR) AF: 0.00170 AC: 26 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.00518

ESP6500AA AF: 0.0149 AC: 63

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00133 AC: 161

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Galactosylceramide beta-galactosidase deficiency (4)
-	-	3	not provided (3)
-	-	1	GALC-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.72		Gain of catalytic residue at T468 (P = 0.0016)
MVP		0.98
MPC		0.56
ClinPred		0.023	T
GERP RS		6.1
Varity_R		0.46
gMVP		0.83
Mutation Taster		=32/68	disease causing

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: rs34134328; hg19: chr14-88414158; COSMIC: COSV99039387; COSMIC: COSV99039387;