NM_004455.3:c.7T>G

Variant names:

• chr1-26022653-T-G
• NM_004455.3:c.7T>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004455.3(EXTL1):​c.7T>G​(p.Ser3Ala) 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. 16/21 in silico tools predict 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: 0.656

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040759563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXTL1	NM_004455.3	c.7T>G	p.Ser3Ala	missense_variant	Exon 1 of 11	ENST00000374280.4	NP_004446.2
EXTL1	XM_005245779.5	c.7T>G	p.Ser3Ala	missense_variant	Exon 1 of 10		XP_005245836.1
EXTL1	XM_017000650.3	c.7T>G	p.Ser3Ala	missense_variant	Exon 1 of 8		XP_016856139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXTL1	ENST00000374280.4	c.7T>G	p.Ser3Ala	missense_variant	Exon 1 of 11	1	NM_004455.3	ENSP00000363398.3
EXTL1	ENST00000481377.5	n.61+2709T>G		intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7T>G (p.S3A) alteration is located in exon 1 (coding exon 1) of the EXTL1 gene. This alteration results from a T to G substitution at nucleotide position 7, causing the serine (S) at amino acid position 3 to be replaced by an alanine (A). 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	0.068
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.95	N
REVEL	Benign	0.19
Sift	Benign	0.64	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.058
MutPred		0.31		Gain of catalytic residue at S3 (P = 0.0075);
MVP		0.35
MPC		0.19
ClinPred		0.11	T
GERP RS		3.5
Varity_R		0.045
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr1-26349144;