1-26023392-A-G

Position:

• chr1-26023392-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004455.3(EXTL1):​c.746A>G​(p.Asp249Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EXTL1 NM_004455.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25567374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXTL1	NM_004455.3	c.746A>G	p.Asp249Gly	missense_variant	1/11	ENST00000374280.4	NP_004446.2
EXTL1	XM_005245779.5	c.746A>G	p.Asp249Gly	missense_variant	1/10		XP_005245836.1
EXTL1	XM_017000650.3	c.746A>G	p.Asp249Gly	missense_variant	1/8		XP_016856139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXTL1	ENST00000374280.4	c.746A>G	p.Asp249Gly	missense_variant	1/11	1	NM_004455.3	ENSP00000363398	P1
EXTL1	ENST00000484339.1	n.204A>G		non_coding_transcript_exon_variant	1/4	3
EXTL1	ENST00000481377.5	n.61+3448A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.746A>G (p.D249G) alteration is located in exon 1 (coding exon 1) of the EXTL1 gene. This alteration results from a A to G substitution at nucleotide position 746, causing the aspartic acid (D) at amino acid position 249 to be replaced by a glycine (G). 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	0.078
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.010	D
Polyphen		0.82	P
Vest4		0.17
MutPred		0.38		Gain of MoRF binding (P = 0.1196);
MVP		0.67
MPC		0.33
ClinPred		0.90	D
GERP RS		2.7
Varity_R		0.35
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-26349883;