chr9-34647702-T-C

Variant names:

• chr9-34647702-T-C
• rs111033680
• NM_000155.4:c.374T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000155.4(GALT):​c.374T>C​(p.Val125Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.30
• Publications: 3 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 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000155.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALT	NM_000155.4	c.374T>C	p.Val125Ala	missense_variant	Exon 4 of 11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.51-130T>C		intron_variant	Intron 2 of 8		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.374T>C	p.Val125Ala	missense_variant	Exon 4 of 11	1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1	c.253-413T>C		intron_variant	Intron 2 of 7	5		ENSP00000451792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.000131 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.027
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	2.0	M
PhyloP100		2.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.82	N
REVEL	Pathogenic	0.67
Sift	Benign	0.29	T
Sift4G	Benign	0.74	T
Polyphen		0.061	B
Vest4		0.78
MutPred		0.80		Gain of disorder (P = 0.0581);
MVP		0.98
MPC		0.92
ClinPred		0.39	T
GERP RS		5.5
Varity_R		0.50
gMVP		0.89
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs111033680; hg19: chr9-34647699;