NM_001033025.3:c.53T>C

Variant names:

• chr1-100877856-A-G
• NM_001033025.3:c.53T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001033025.3(EXTL2):​c.53T>C​(p.Val18Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EXTL2 NM_001033025.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1737678).

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.53T>C	p.Val18Ala	missense	Exon 3 of 5	NP_001028197.1	Q9UBQ6
	EXTL2	NM_001261441.2		c.77T>C	p.Val26Ala	missense	Exon 4 of 6	NP_001248370.1
	EXTL2	NM_001439.4		c.53T>C	p.Val18Ala	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.53T>C	p.Val18Ala	missense	Exon 3 of 5	ENSP00000359132.3	Q9UBQ6
	EXTL2	ENST00000370113.7	TSL:1	c.53T>C	p.Val18Ala	missense	Exon 3 of 5	ENSP00000359131.3	Q9UBQ6
	EXTL2	ENST00000886545.1		c.77T>C	p.Val26Ala	missense	Exon 4 of 6	ENSP00000556603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447828 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720668

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111514

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0092	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.27
Sift	Benign	0.032	D
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.095
MutPred		0.34		Loss of sheet (P = 0.0025)
MVP		0.70
MPC		0.19
ClinPred		0.047	T
GERP RS		1.8
Varity_R		0.024
gMVP		0.53
Mutation Taster		=91/9	polymorphism

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

hg19: chr1-101343412;