chr14-87965554-C-T

Variant names:

• chr14-87965554-C-T
• rs12888666
• NM_000153.4:c.984G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000153.4(GALC):​c.984G>A​(p.Gln328Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,612,286 control chromosomes in the GnomAD database, including 108,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8463 hom., cov: 32)
  • Exomes 𝑓: 0.36 (100131 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.68
• Publications: 36 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

LOC124903355 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 14-87965554-C-T is Benign according to our data. Variant chr14-87965554-C-T is described in ClinVar as Benign. ClinVar VariationId is 92513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 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.984G>A	p.Gln328Gln	synonymous	Exon 9 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.915G>A	p.Gln305Gln	synonymous	Exon 8 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.906G>A	p.Gln302Gln	synonymous	Exon 9 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.984G>A	p.Gln328Gln	synonymous	Exon 9 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.972G>A	p.Gln324Gln	synonymous	Exon 9 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.974G>A		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46761 AN: 151784 Hom.: 8463 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.326

GnomAD2 exomes AF: 0.390 AC: 97013 AN: 248956 AF XY: 0.392

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.519

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.596

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.384

GnomAD4 exome AF: 0.364 AC: 531419 AN: 1460384 Hom.: 100131 Cov.: 35 AF XY: 0.366 AC XY: 265909 AN XY: 726546

African (AFR) AF: 0.113 AC: 3786 AN: 33440

American (AMR) AF: 0.507 AC: 22622 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 9856 AN: 26082

East Asian (EAS) AF: 0.612 AC: 24257 AN: 39668

South Asian (SAS) AF: 0.429 AC: 37019 AN: 86232

European-Finnish (FIN) AF: 0.343 AC: 18299 AN: 53404

Middle Eastern (MID) AF: 0.371 AC: 2137 AN: 5758

European-Non Finnish (NFE) AF: 0.353 AC: 391676 AN: 1110830

Other (OTH) AF: 0.361 AC: 21767 AN: 60316

GnomAD4 genome AF: 0.308 AC: 46763 AN: 151902 Hom.: 8463 Cov.: 32 AF XY: 0.314 AC XY: 23324 AN XY: 74230

African (AFR) AF: 0.125 AC: 5170 AN: 41498

American (AMR) AF: 0.438 AC: 6667 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1285 AN: 3472

East Asian (EAS) AF: 0.582 AC: 2988 AN: 5138

South Asian (SAS) AF: 0.413 AC: 1994 AN: 4824

European-Finnish (FIN) AF: 0.346 AC: 3644 AN: 10540

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.352 AC: 23900 AN: 67912

Other (OTH) AF: 0.324 AC: 681 AN: 2104

Alfa AF: 0.346 Hom.: 18733

Bravo AF: 0.310

Asia WGS AF: 0.408 AC: 1420 AN: 3478

EpiCase AF: 0.367

EpiControl AF: 0.371

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
BayesDel_noAF	Benign	-0.23
CADD	Benign	6.8
DANN	Benign	0.77
PhyloP100		1.7
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: rs12888666; hg19: chr14-88431898; COSMIC: COSV54327408; COSMIC: COSV54327408;