rs111033692

Variant names:

• chr9-34647878-A-C
• rs111033692
• NM_000155.4:c.424A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-34647878-A-C
• chr9-34647878-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The NM_000155.4(GALT):​c.424A>C​(p.Met142Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M142V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.49
• Publications: 0 publications found

Genes affected

GALT (HGNC:4135): (galactose-1-phosphate uridylyltransferase) Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

GALT Gene-Disease associations (from GenCC):

• classic galactosemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• galactosemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

ENSG00000258728 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000155.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-34647878-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2573375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 104 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 0.91493 (below the threshold of 3.09). Trascript score misZ: 1.8645 (below the threshold of 3.09). GenCC associations: The gene is linked to galactosemia, classic galactosemia.
• PP5: Variant 9-34647878-A-C is Pathogenic according to our data. Variant chr9-34647878-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3014445.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000155.4. 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
	GALT	NM_000155.4	MANE Select	c.424A>C	p.Met142Leu	missense	Exon 5 of 11	NP_000146.2
	GALT	NM_001258332.2		c.97A>C	p.Met33Leu	missense	Exon 3 of 9	NP_001245261.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALT	ENST00000378842.8	TSL:1 MANE Select	c.424A>C	p.Met142Leu	missense	Exon 5 of 11	ENSP00000368119.4
	ENSG00000258728	ENST00000556278.1	TSL:5	c.253-237A>C		intron	N/A	ENSP00000451792.1
	GALT	ENST00000902340.1		c.463A>C	p.Met155Leu	missense	Exon 4 of 10	ENSP00000572399.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L
PhyloP100		6.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.77
Sift	Benign	1.0	T
Sift4G	Benign	0.72	T
Polyphen		0.31	B
Vest4		0.58
MutPred		0.72		Gain of catalytic residue at M142 (P = 0.0974)
MVP		0.96
MPC		0.74
ClinPred		0.48	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.95
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs111033692; hg19: chr9-34647875;