rs398607

Variant names:

• chr14-87941544-A-G
• rs398607
• NM_000153.4:c.1685T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-87941544-A-G
• chr14-87941544-A-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.1685T>C​(p.Ile562Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,576,428 control chromosomes in the GnomAD database, including 174,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I562K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.49 (19109 hom., cov: 32)
  • Exomes 𝑓: 0.46 (155737 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts B:11 O:5
• Conservation: PhyloP100: 9.29
• Publications: 67 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 -15 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, 4 uncertain in NM_000153.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-87941544-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2502893.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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=4.962683E-4).
• BP6: Variant 14-87941544-A-G is Benign according to our data. Variant chr14-87941544-A-G is described in ClinVar as Benign|other. ClinVar VariationId is 92497.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.1685T>C	p.Ile562Thr	missense	Exon 15 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1616T>C	p.Ile539Thr	missense	Exon 14 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1607T>C	p.Ile536Thr	missense	Exon 15 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.1685T>C	p.Ile562Thr	missense	Exon 15 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1646T>C	p.Ile549Thr	missense	Exon 14 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1619T>C	p.Ile540Thr	missense	Exon 15 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74706 AN: 151734 Hom.: 19079 Cov.: 32

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.486

GnomAD2 exomes AF: 0.433 AC: 107634 AN: 248542 AF XY: 0.435

Gnomad AFR exome AF: 0.610

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.485

Gnomad EAS exome AF: 0.175

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.462 AC: 658766 AN: 1424576 Hom.: 155737 Cov.: 30 AF XY: 0.462 AC XY: 328556 AN XY: 711174

African (AFR) AF: 0.610 AC: 19894 AN: 32616

American (AMR) AF: 0.326 AC: 14522 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 12462 AN: 25788

East Asian (EAS) AF: 0.195 AC: 7710 AN: 39480

South Asian (SAS) AF: 0.418 AC: 35699 AN: 85458

European-Finnish (FIN) AF: 0.470 AC: 25057 AN: 53354

Middle Eastern (MID) AF: 0.439 AC: 2499 AN: 5696

European-Non Finnish (NFE) AF: 0.477 AC: 514077 AN: 1078538

Other (OTH) AF: 0.454 AC: 26846 AN: 59092

GnomAD4 genome AF: 0.493 AC: 74789 AN: 151852 Hom.: 19109 Cov.: 32 AF XY: 0.488 AC XY: 36174 AN XY: 74186

African (AFR) AF: 0.603 AC: 24972 AN: 41424

American (AMR) AF: 0.396 AC: 6038 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 1703 AN: 3470

East Asian (EAS) AF: 0.187 AC: 959 AN: 5136

South Asian (SAS) AF: 0.425 AC: 2046 AN: 4818

European-Finnish (FIN) AF: 0.476 AC: 5033 AN: 10582

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.478 AC: 32410 AN: 67868

Other (OTH) AF: 0.491 AC: 1037 AN: 2114

Alfa AF: 0.474 Hom.: 59431

Bravo AF: 0.489

TwinsUK AF: 0.497 AC: 1843

ALSPAC AF: 0.485 AC: 1869

ESP6500AA AF: 0.614 AC: 2248

ESP6500EA AF: 0.481 AC: 3934

ExAC AF: 0.440 AC: 53173

Asia WGS AF: 0.398 AC: 1382 AN: 3478

EpiCase AF: 0.465

EpiControl AF: 0.463

ClinVar

ClinVar submissions

Significance: Benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Galactosylceramide beta-galactosidase deficiency (8)
-	-	4	not specified (4)
-	-	2	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.00050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		9.3
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.46	P
Vest4		0.56
MPC		0.20
ClinPred		0.039	T
GERP RS		5.7
Varity_R		0.20
gMVP		0.88
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs398607; hg19: chr14-88407888; COSMIC: COSV54324831;