Genetic Variant NM_004455.3:c.557C>A (chr1-26023203-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004455.3(EXTL1):c.557C>A(p.Thr186Lys) 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 1,460,268 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. 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. T186M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EXTL1
NM_004455.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.132

Publications

1 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: 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=0.11371204).

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.557C>A	p.Thr186Lys	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.557C>A	p.Thr186Lys	missense	Exon 1 of 11	ENSP00000363398.3	Q92935
EXTL1	ENST00000882621.1		c.557C>A	p.Thr186Lys	missense	Exon 1 of 11	ENSP00000552680.1
EXTL1	ENST00000882616.1		c.557C>A	p.Thr186Lys	missense	Exon 1 of 10	ENSP00000552675.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460268

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111046

Other (OTH)

AF:

0.0000166

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Benign

9.5

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.37

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.40

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.11

MetaSVM

Uncertain

-0.072

MutationAssessor

Benign

1.7

PhyloP100

-0.13

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.3

REVEL

Benign

0.25

Sift

Benign

0.062

Sift4G

Benign

0.16

Polyphen

0.054

Vest4

0.090

MutPred

0.58

Gain of ubiquitination at T186 (P = 0.0192)

MVP

0.37

MPC

0.29

ClinPred

0.15

GERP RS

1.3

Varity_R

0.076

gMVP

0.58

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over