Variant 1-26029695-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004455.3(EXTL1):c.969G>C(p.Arg323Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,457,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

EXTL1
NM_004455.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.52

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EXTL1	NM_004455.3 linkuse as main transcript	c.969G>C	p.Arg323Ser	missense_variant	3/11	ENST00000374280.4	NP_004446.2
EXTL1	XM_017000650.3 linkuse as main transcript	c.969G>C	p.Arg323Ser	missense_variant	3/8		XP_016856139.1
EXTL1	XM_005245779.5 linkuse as main transcript	c.873+409G>C		intron_variant			XP_005245836.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EXTL1	ENST00000374280.4 linkuse as main transcript	c.969G>C	p.Arg323Ser	missense_variant	3/11	1	NM_004455.3	ENSP00000363398	P1
EXTL1	ENST00000481377.5 linkuse as main transcript	n.251G>C		non_coding_transcript_exon_variant	3/6	3
EXTL1	ENST00000484339.1 linkuse as main transcript	n.331+409G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000892

AC:

AN:

1457266

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724854

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

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

Feb 27, 2024

The c.969G>C (p.R323S) alteration is located in exon 3 (coding exon 3) of the EXTL1 gene. This alteration results from a G to C substitution at nucleotide position 969, causing the arginine (R) at amino acid position 323 to be replaced by a serine (S). 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

0.28

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

0.12

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.82

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.79

MutPred

0.46

Loss of solvent accessibility (P = 0.0606);

MVP

0.79

MPC

0.91

ClinPred

1.0

GERP RS

0.55

Varity_R

0.75

gMVP

0.85

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