Variant 1-26023011-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004455.3(EXTL1):c.365G>A(p.Arg122His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

EXTL1
NM_004455.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.50

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EXTL1	NM_004455.3 linkuse as main transcript	c.365G>A	p.Arg122His	missense_variant	1/11	ENST00000374280.4	NP_004446.2
EXTL1	XM_005245779.5 linkuse as main transcript	c.365G>A	p.Arg122His	missense_variant	1/10		XP_005245836.1
EXTL1	XM_017000650.3 linkuse as main transcript	c.365G>A	p.Arg122His	missense_variant	1/8		XP_016856139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXTL1	ENST00000374280.4 linkuse as main transcript	c.365G>A	p.Arg122His	missense_variant	1/11	1	NM_004455.3	ENSP00000363398	P1
EXTL1	ENST00000481377.5 linkuse as main transcript	n.61+3067G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251370

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2022

The c.365G>A (p.R122H) alteration is located in exon 1 (coding exon 1) of the EXTL1 gene. This alteration results from a G to A substitution at nucleotide position 365, causing the arginine (R) at amino acid position 122 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.49

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0090

Polyphen

0.39

Vest4

0.12

MutPred

0.84

Loss of methylation at R122 (P = 0.0635);

MVP

0.63

MPC

0.31

ClinPred

0.86

GERP RS

1.4

Varity_R

0.25

gMVP

0.69

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over