14-87992951-C-T

Variant names:

• chr14-87992951-C-T
• rs189853941
• NM_000153.4:c.195+19G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000153.4(GALC):​c.195+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,509,366 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (14 hom.)
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0400
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-87992951-C-T is Benign according to our data. Variant chr14-87992951-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

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.195+19G>A		intron	N/A	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.195+19G>A		intron	N/A	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.117+432G>A		intron	N/A	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.195+19G>A		intron	N/A	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.183+19G>A		intron	N/A	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.185+19G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 297 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00371

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00167 AC: 190 AN: 113460 AF XY: 0.00165

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.000422

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000690

Gnomad NFE exome AF: 0.00296

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00318 AC: 4322 AN: 1357082 Hom.: 14 Cov.: 33 AF XY: 0.00309 AC XY: 2068 AN XY: 670198

African (AFR) AF: 0.000548 AC: 15 AN: 27382

American (AMR) AF: 0.00157 AC: 54 AN: 34374

Ashkenazi Jewish (ASJ) AF: 0.000587 AC: 14 AN: 23842

East Asian (EAS) AF: 0.00 AC: 0 AN: 31736

South Asian (SAS) AF: 0.000327 AC: 25 AN: 76534

European-Finnish (FIN) AF: 0.000624 AC: 21 AN: 33678

Middle Eastern (MID) AF: 0.000755 AC: 3 AN: 3976

European-Non Finnish (NFE) AF: 0.00373 AC: 3987 AN: 1069280

Other (OTH) AF: 0.00361 AC: 203 AN: 56280

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74460

African (AFR) AF: 0.000601 AC: 25 AN: 41578

American (AMR) AF: 0.000588 AC: 9 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00371 AC: 252 AN: 68000

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00325 Hom.: 1

Bravo AF: 0.00203

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Galactosylceramide beta-galactosidase deficiency (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.1
DANN	Benign	0.94
PhyloP100		-0.040
PromoterAI		-0.088	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs189853941; hg19: chr14-88459295;