Genetic Variant EXTL1:p.Gly223Arg (chr1-26023313-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004455.3(EXTL1):c.667G>A(p.Gly223Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,551,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

EXTL1
NM_004455.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.10

Publications

3 publications found

Variant links:

Genes affected

EXTL1 (HGNC:3515): (exostosin like glycosyltransferase 1) This gene is a member of the multiple exostoses (EXT) family of glycosyltransferases, which function in the chain polymerization of heparan sulfate and heparin. The encoded protein harbors alpha 1,4- N-acetylglucosaminyltransferase activity, and is involved in chain elongation of heparan sulfate and possibly heparin. [provided by RefSeq, Jul 2008]

EXTL1 links:

ENSG00000310101 (HGNC:):

ENSG00000310101 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062825084).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004455.3. 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
	EXTL1	NM_004455.3	MANE Select	c.667G>A	p.Gly223Arg	missense	Exon 1 of 11	NP_004446.2	Q92935

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXTL1	ENST00000374280.4	TSL:1 MANE Select	c.667G>A	p.Gly223Arg	missense	Exon 1 of 11	ENSP00000363398.3	Q92935
EXTL1	ENST00000882621.1		c.667G>A	p.Gly223Arg	missense	Exon 1 of 11	ENSP00000552680.1
EXTL1	ENST00000882616.1		c.667G>A	p.Gly223Arg	missense	Exon 1 of 10	ENSP00000552675.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000156

AC:

AN:

192124

AF XY:

0.0000291

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000346

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000293

AC:

AN:

1399540

Hom.:

Cov.:

AF XY:

0.0000320

AC XY:

AN XY:

688546

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31902

American (AMR)

AF:

0.00

AC:

AN:

38316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22184

East Asian (EAS)

AF:

0.00

AC:

AN:

38842

South Asian (SAS)

AF:

0.00

AC:

AN:

76754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49938

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5458

European-Non Finnish (NFE)

AF:

0.0000306

AC:

AN:

1078602

Other (OTH)

AF:

0.000122

AC:

AN:

57544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000166

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.5

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.18

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.65

M_CAP

Benign

0.015

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.12

PhyloP100

1.1

PrimateAI

Benign

0.35

PROVEAN

Benign

2.0

REVEL

Benign

0.26

Sift

Benign

0.89

Sift4G

Benign

0.87

Polyphen

0.0070

Vest4

0.061

MutPred

0.69

Loss of catalytic residue at V224 (P = 0.0295)

MVP

0.32

MPC

0.32

ClinPred

0.050

GERP RS

-4.1

Varity_R

0.12

gMVP

0.51

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over