1-23796722-T-C

Variant names:

• chr1-23796722-T-C
• rs28940884
• NM_001008216.2:c.770A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001008216.2(GALE):​c.770A>G​(p.Lys257Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,138 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).

• Frequency:
  • Genomes: 𝑓 0.0056 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (14 hom.)
• Consequence: GALE NM_001008216.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:2 U:4 B:6 O:1
• Conservation: PhyloP100: 7.35
• Publications: 16 publications found

Genes affected

GALE (HGNC:4116): (UDP-galactose-4-epimerase) This gene encodes UDP-galactose-4-epimerase which catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose, and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The bifunctional nature of the enzyme has the important metabolic consequence that mutant cells (or individuals) are dependent not only on exogenous galactose, but also on exogenous N-acetylgalactosamine as a necessary precursor for the synthesis of glycoproteins and glycolipids. Mutations in this gene result in epimerase-deficiency galactosemia, also referred to as galactosemia type 3, a disease characterized by liver damage, early-onset cataracts, deafness and cognitive disability, with symptoms ranging from mild ('peripheral' form) to severe ('generalized' form). Multiple alternatively spliced transcripts encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

GALE Gene-Disease associations (from GenCC):

• galactose epimerase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.32246 (below the threshold of 3.09). Trascript score misZ: 0.87424 (below the threshold of 3.09). GenCC associations: The gene is linked to galactose epimerase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00929606).
• BP6: Variant 1-23796722-T-C is Benign according to our data. Variant chr1-23796722-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity|other. ClinVar VariationId is 3679.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0056 (852/152276) while in subpopulation AFR AF = 0.0194 (805/41544). AF 95% confidence interval is 0.0183. There are 10 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008216.2. 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
	GALE	NM_001008216.2	MANE Select	c.770A>G	p.Lys257Arg	missense	Exon 9 of 12	NP_001008217.1	A0A384NL38
	GALE	NM_000403.4		c.770A>G	p.Lys257Arg	missense	Exon 9 of 12	NP_000394.2	Q14376-1
	GALE	NM_001127621.2		c.770A>G	p.Lys257Arg	missense	Exon 8 of 11	NP_001121093.1	A0A384NL38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALE	ENST00000617979.5	TSL:1 MANE Select	c.770A>G	p.Lys257Arg	missense	Exon 9 of 12	ENSP00000483375.1	Q14376-1
	GALE	ENST00000374497.7	TSL:1	c.770A>G	p.Lys257Arg	missense	Exon 9 of 12	ENSP00000363621.3	Q14376-1
	GALE	ENST00000854948.1		c.770A>G	p.Lys257Arg	missense	Exon 8 of 11	ENSP00000525007.1

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 852 AN: 152158 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00141 AC: 351 AN: 248990 AF XY: 0.00108

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.000758

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000727 AC: 1062 AN: 1460862 Hom.: 14 Cov.: 35 AF XY: 0.000644 AC XY: 468 AN XY: 726612

African (AFR) AF: 0.0200 AC: 669 AN: 33464

American (AMR) AF: 0.000921 AC: 41 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000255 AC: 283 AN: 1111560

Other (OTH) AF: 0.00113 AC: 68 AN: 60380

GnomAD4 genome AF: 0.00560 AC: 852 AN: 152276 Hom.: 10 Cov.: 32 AF XY: 0.00522 AC XY: 389 AN XY: 74460

African (AFR) AF: 0.0194 AC: 805 AN: 41544

American (AMR) AF: 0.00163 AC: 25 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68026

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00272 Hom.: 9

Bravo AF: 0.00594

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00175 AC: 213

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; other

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	2	UDPglucose-4-epimerase deficiency (5)
-	2	1	not provided (4)
-	-	3	not specified (3)
-	1	-	GALE-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.040
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.71	N
PhyloP100		7.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.62
Sift	Benign	0.20	T
Sift4G	Benign	0.19	T
Polyphen		0.057	B
Vest4		0.81
MVP		0.90
MPC		0.17
ClinPred		0.027	T
GERP RS		5.7
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.79
gMVP		0.64
Mutation Taster		=34/66	disease causing

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: rs28940884; hg19: chr1-24123212;