rs34362748

Variant names:

• chr14-87976368-C-T
• rs34362748
• NM_000153.4:c.742G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-87976368-C-T
• chr14-87976368-C-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.742G>A​(p.Asp248Asn) variant causes a missense change. The variant allele was found at a frequency of 0.142 in 1,613,138 control chromosomes in the GnomAD database, including 17,561 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. D248Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1143 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16418 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts U:1 B:8 O:3
• Conservation: PhyloP100: 5.68
• Publications: 47 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.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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=0.0022206604).
• BP6: Variant 14-87976368-C-T is Benign according to our data. Variant chr14-87976368-C-T is described in ClinVar as Benign|other. ClinVar VariationId is 92509.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: 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.742G>A	p.Asp248Asn	missense	Exon 7 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.673G>A	p.Asp225Asn	missense	Exon 6 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.664G>A	p.Asp222Asn	missense	Exon 7 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.742G>A	p.Asp248Asn	missense	Exon 7 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.730G>A	p.Asp244Asn	missense	Exon 7 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.732G>A		non_coding_transcript_exon	Exon 7 of 10

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17197 AN: 152054 Hom.: 1140 Cov.: 32

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0956

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.126 AC: 31486 AN: 249288 AF XY: 0.126

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.00195

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.145 AC: 211284 AN: 1460966 Hom.: 16418 Cov.: 32 AF XY: 0.143 AC XY: 104237 AN XY: 726850

African (AFR) AF: 0.0347 AC: 1163 AN: 33476

American (AMR) AF: 0.146 AC: 6527 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3106 AN: 26132

East Asian (EAS) AF: 0.00159 AC: 63 AN: 39666

South Asian (SAS) AF: 0.102 AC: 8798 AN: 86248

European-Finnish (FIN) AF: 0.163 AC: 8675 AN: 53304

Middle Eastern (MID) AF: 0.162 AC: 933 AN: 5766

European-Non Finnish (NFE) AF: 0.157 AC: 173970 AN: 1111290

Other (OTH) AF: 0.133 AC: 8049 AN: 60368

GnomAD4 genome AF: 0.113 AC: 17206 AN: 152172 Hom.: 1143 Cov.: 32 AF XY: 0.114 AC XY: 8446 AN XY: 74390

African (AFR) AF: 0.0400 AC: 1662 AN: 41544

American (AMR) AF: 0.130 AC: 1992 AN: 15284

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

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

South Asian (SAS) AF: 0.0954 AC: 460 AN: 4820

European-Finnish (FIN) AF: 0.156 AC: 1652 AN: 10582

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

European-Non Finnish (NFE) AF: 0.156 AC: 10621 AN: 67984

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

Alfa AF: 0.135 Hom.: 3713

Bravo AF: 0.107

TwinsUK AF: 0.147 AC: 546

ALSPAC AF: 0.153 AC: 590

ESP6500AA AF: 0.0444 AC: 171

ESP6500EA AF: 0.152 AC: 1259

ExAC AF: 0.124 AC: 15018

Asia WGS AF: 0.0550 AC: 191 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.155

ClinVar

ClinVar submissions

Significance: Benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (4)
-	-	3	not specified (3)
-	-	2	Galactosylceramide beta-galactosidase deficiency (4)
-	-	1	GALC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.4	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.62
Sift	Benign	0.039	D
Sift4G	Uncertain	0.053	T
Polyphen		0.63	P
Vest4		0.38
MPC		0.39
ClinPred		0.067	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.91
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs34362748; hg19: chr14-88442712; COSMIC: COSV54330950; COSMIC: COSV54330950;