rs11552556

Variant names:

• chr14-87986601-G-A
• rs11552556
• NM_000153.4:c.330C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-87986601-G-A
• chr14-87986601-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001424074.1(GALC):​c.-19C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.04 in 1,602,176 control chromosomes in the GnomAD database, including 1,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (126 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1423 hom.)
• Consequence: GALC NM_001424074.1 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00003664
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.75
• Publications: 12 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, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 14-87986601-G-A is Benign according to our data. Variant chr14-87986601-G-A is described in ClinVar as Benign. ClinVar VariationId is 92502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.031 (4712/152096) while in subpopulation NFE AF = 0.0465 (3162/67992). AF 95% confidence interval is 0.0452. There are 126 homozygotes in GnomAd4. There are 2282 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 126 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424074.1. 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.330C>T	p.Asp110Asp	splice_region synonymous	Exon 4 of 17	NP_000144.2
	GALC	NM_001424074.1		c.-19C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 17	NP_001411003.1
	GALC	NM_001424075.1		c.-19C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 18	NP_001411004.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.330C>T	p.Asp110Asp	splice_region synonymous	Exon 4 of 17	ENSP00000261304.2
	GALC	ENST00000622264.4	TSL:1	c.318C>T	p.Asp106Asp	splice_region synonymous	Exon 4 of 10	ENSP00000480649.1
	GALC	ENST00000474294.6	TSL:1	n.320C>T		splice_region non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4711 AN: 151978 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.00846

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.0501

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0465

Gnomad OTH AF: 0.0345

GnomAD2 exomes AF: 0.0331 AC: 8216 AN: 248540 AF XY: 0.0340

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0493

Gnomad EAS exome AF: 0.00117

Gnomad FIN exome AF: 0.0565

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0309

GnomAD4 exome AF: 0.0410 AC: 59415 AN: 1450080 Hom.: 1423 Cov.: 28 AF XY: 0.0408 AC XY: 29482 AN XY: 722150

African (AFR) AF: 0.00518 AC: 172 AN: 33204

American (AMR) AF: 0.0170 AC: 757 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 1304 AN: 26064

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39646

South Asian (SAS) AF: 0.0213 AC: 1831 AN: 85970

European-Finnish (FIN) AF: 0.0528 AC: 2817 AN: 53328

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5754

European-Non Finnish (NFE) AF: 0.0458 AC: 50430 AN: 1101468

Other (OTH) AF: 0.0334 AC: 2005 AN: 59998

GnomAD4 genome AF: 0.0310 AC: 4712 AN: 152096 Hom.: 126 Cov.: 32 AF XY: 0.0307 AC XY: 2282 AN XY: 74350

African (AFR) AF: 0.00844 AC: 350 AN: 41492

American (AMR) AF: 0.0183 AC: 279 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3470

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5162

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4824

European-Finnish (FIN) AF: 0.0501 AC: 530 AN: 10574

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0465 AC: 3162 AN: 67992

Other (OTH) AF: 0.0337 AC: 71 AN: 2106

Alfa AF: 0.0405 Hom.: 488

Bravo AF: 0.0284

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0465

EpiControl AF: 0.0442

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Galactosylceramide beta-galactosidase deficiency (5)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.56
PhyloP100		3.8
Mutation Taster		=51/49	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.11
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: rs11552556; hg19: chr14-88452945; COSMIC: COSV54325605; COSMIC: COSV54325605;