1-100874231-G-C

Variant names:

• chr1-100874231-G-C
• rs147366080
• NM_001033025.3:c.704C>G

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.704C>G​(p.Ala235Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. A235V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EXTL2 NM_001033025.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06
• 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=0.1705128).

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.704C>G	p.Ala235Gly	missense	Exon 5 of 5	NP_001028197.1	Q9UBQ6
	EXTL2	NM_001261441.2		c.728C>G	p.Ala243Gly	missense	Exon 6 of 6	NP_001248370.1
	EXTL2	NM_001439.4		c.704C>G	p.Ala235Gly	missense	Exon 5 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.704C>G	p.Ala235Gly	missense	Exon 5 of 5	ENSP00000359132.3	Q9UBQ6
	EXTL2	ENST00000370113.7	TSL:1	c.704C>G	p.Ala235Gly	missense	Exon 5 of 5	ENSP00000359131.3	Q9UBQ6
	EXTL2	ENST00000886545.1		c.728C>G	p.Ala243Gly	missense	Exon 6 of 6	ENSP00000556603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460702 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726636

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111402

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.080
Sift	Benign	0.37	T
Sift4G	Benign	0.24	T
Polyphen		0.034	B
Vest4		0.31
MutPred		0.43		Loss of stability (P = 0.0548)
MVP		0.69
MPC		0.18
ClinPred		0.39	T
GERP RS		5.1
Varity_R		0.067
gMVP		0.21
Mutation Taster		=89/11	polymorphism

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: rs147366080; hg19: chr1-101339787;