3-38374462-C-G

Variant names:

• chr3-38374462-C-G
• rs1217748341
• NM_005108.4:c.848C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005108.4(XYLB):​c.848C>G​(p.Ala283Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A283V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: XYLB NM_005108.4 missense, splice_region
• Scores: Splicing: ADA: 0.9690
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92
• Publications: 0 publications found

Genes affected

XYLB (HGNC:12839): (xylulokinase) The protein encoded by this gene shares 22% sequence identity with Hemophilus influenzae xylulokinase, and even higher identity to other gene products in C.elegans (45%) and yeast (31-35%), which are thought to belong to a family of enzymes that include fucokinase, gluconokinase, glycerokinase and xylulokinase. These proteins play important roles in energy metabolism. [provided by RefSeq, Aug 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34993672).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005108.4. 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
	XYLB	NM_005108.4	MANE Select	c.848C>G	p.Ala283Gly	missense splice_region	Exon 11 of 19	NP_005099.2
	XYLB	NM_001349178.2		c.848C>G	p.Ala283Gly	missense splice_region	Exon 11 of 20	NP_001336107.1
	XYLB	NM_001349179.2		c.437C>G	p.Ala146Gly	missense splice_region	Exon 9 of 17	NP_001336108.1	O75191-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XYLB	ENST00000207870.8	TSL:1 MANE Select	c.848C>G	p.Ala283Gly	missense splice_region	Exon 11 of 19	ENSP00000207870.3	O75191-1
	XYLB	ENST00000854437.1		c.848C>G	p.Ala283Gly	missense splice_region	Exon 11 of 20	ENSP00000524496.1
	XYLB	ENST00000650590.1		c.767C>G	p.Ala256Gly	missense splice_region	Exon 10 of 18	ENSP00000496840.1	A0A3B3IRM4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		3.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.16
Sift	Benign	0.34	T
Sift4G	Benign	0.28	T
Polyphen		0.26	B
Vest4		0.51
MutPred		0.71		Gain of disorder (P = 0.0683)
MVP		0.47
MPC		0.19
ClinPred		0.85	D
GERP RS		5.6
Varity_R		0.51
gMVP		0.48
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.14		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: rs1217748341; hg19: chr3-38415953;