1-100877641-G-C

Variant names:

• chr1-100877641-G-C
• rs753971587
• NM_001033025.3:c.268C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001033025.3(EXTL2):​c.268C>G​(p.Pro90Ala) variant causes a missense change involving the alteration of a 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P90S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXTL2 NM_001033025.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.52
• Publications: 1 publications found

Genes affected

EXTL2 (HGNC:3516): (exostosin like glycosyltransferase 2) Enables alpha-1,4-N-acetylgalactosaminyltransferase activity and glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity. Involved in N-acetylglucosamine metabolic process and UDP-N-acetylgalactosamine metabolic process. Located in cytosol; endoplasmic reticulum; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033025.3. 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
	EXTL2	NM_001033025.3	MANE Select	c.268C>G	p.Pro90Ala	missense	Exon 3 of 5	NP_001028197.1	Q9UBQ6
	EXTL2	NM_001261441.2		c.292C>G	p.Pro98Ala	missense	Exon 4 of 6	NP_001248370.1
	EXTL2	NM_001439.4		c.268C>G	p.Pro90Ala	missense	Exon 3 of 5	NP_001430.1	Q9UBQ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXTL2	ENST00000370114.8	TSL:1 MANE Select	c.268C>G	p.Pro90Ala	missense	Exon 3 of 5	ENSP00000359132.3	Q9UBQ6
	EXTL2	ENST00000370113.7	TSL:1	c.268C>G	p.Pro90Ala	missense	Exon 3 of 5	ENSP00000359131.3	Q9UBQ6
	EXTL2	ENST00000886545.1		c.292C>G	p.Pro98Ala	missense	Exon 4 of 6	ENSP00000556603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.82
MutPred		0.77		Loss of loop (P = 0.1242)
MVP		0.93
MPC		0.63
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.49
Mutation Taster		=38/62	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: rs753971587; hg19: chr1-101343197;