rs111887056

Variant names:

• chr14-87993104-C-G
• rs111887056
• NM_000153.4:c.61G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-87993104-C-G
• chr14-87993104-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.61G>C​(p.Ala21Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,586,544 control chromosomes in the GnomAD database, including 16,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1112 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15567 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.562
• Publications: 28 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 -19 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: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018750429).
• BP6: Variant 14-87993104-C-G is Benign according to our data. Variant chr14-87993104-C-G is described in ClinVar as Benign. ClinVar VariationId is 92508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 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.61G>C	p.Ala21Pro	missense	Exon 1 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.61G>C	p.Ala21Pro	missense	Exon 1 of 16	NP_001188330.1	P54803-3
	GALC	NM_001424072.1		c.-210G>C		5_prime_UTR	Exon 1 of 18	NP_001411001.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.61G>C	p.Ala21Pro	missense	Exon 1 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.49G>C	p.Ala17Pro	missense	Exon 1 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.51G>C		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17026 AN: 152156 Hom.: 1109 Cov.: 33

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0947

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.115 AC: 21968 AN: 190848 AF XY: 0.114

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.000725

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.142 AC: 203924 AN: 1434276 Hom.: 15567 Cov.: 33 AF XY: 0.141 AC XY: 100074 AN XY: 710896

African (AFR) AF: 0.0341 AC: 1127 AN: 33054

American (AMR) AF: 0.139 AC: 5735 AN: 41128

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3008 AN: 25622

East Asian (EAS) AF: 0.00124 AC: 48 AN: 38578

South Asian (SAS) AF: 0.100 AC: 8314 AN: 82906

European-Finnish (FIN) AF: 0.158 AC: 7762 AN: 49084

Middle Eastern (MID) AF: 0.158 AC: 889 AN: 5614

European-Non Finnish (NFE) AF: 0.154 AC: 169279 AN: 1099038

Other (OTH) AF: 0.131 AC: 7762 AN: 59252

GnomAD4 genome AF: 0.112 AC: 17035 AN: 152268 Hom.: 1112 Cov.: 33 AF XY: 0.112 AC XY: 8361 AN XY: 74464

African (AFR) AF: 0.0396 AC: 1645 AN: 41566

American (AMR) AF: 0.130 AC: 1994 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5174

South Asian (SAS) AF: 0.0946 AC: 457 AN: 4830

European-Finnish (FIN) AF: 0.154 AC: 1638 AN: 10618

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.154 AC: 10488 AN: 67998

Other (OTH) AF: 0.108 AC: 228 AN: 2110

Alfa AF: 0.140 Hom.: 554

Bravo AF: 0.106

TwinsUK AF: 0.139 AC: 517

ALSPAC AF: 0.146 AC: 564

ESP6500AA AF: 0.0366 AC: 109

ESP6500EA AF: 0.115 AC: 777

ExAC AF: 0.0887 AC: 10059

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Galactosylceramide beta-galactosidase deficiency (5)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.56
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.51
Sift	Benign	0.072	T
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.17
MPC		0.66
ClinPred		0.033	T
GERP RS		3.2
PromoterAI		0.025	Neutral
Varity_R		0.14
gMVP		0.74
Mutation Taster		=96/4	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: rs111887056; hg19: chr14-88459448; COSMIC: COSV54324700; COSMIC: COSV54324700;