1-100874172-G-T

Variant names:

• chr1-100874172-G-T
• NM_001033025.3:c.763C>A

Variant summary

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

The NM_001033025.3(EXTL2):​c.763C>A​(p.His255Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXTL2 NM_001033025.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

Genes affected

EXTL2 (HGNC:3516): (exostosin like glycosyltransferase 2) Enables alpha-1,4-N-acetylgalactosaminyltransferase activity and glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity. Involved in N-acetylglucosamine metabolic process and UDP-N-acetylgalactosamine metabolic process. Located in cytosol; endoplasmic reticulum; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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 rank	MANE	Protein	UniProt
EXTL2	NM_001033025.3	c.763C>A	p.His255Asn	missense_variant	Exon 5 of 5	ENST00000370114.8	NP_001028197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXTL2	ENST00000370114.8	c.763C>A	p.His255Asn	missense_variant	Exon 5 of 5	1	NM_001033025.3	ENSP00000359132.3
EXTL2	ENST00000370113.7	c.763C>A	p.His255Asn	missense_variant	Exon 5 of 5	1		ENSP00000359131.3
EXTL2	ENST00000450240.2	c.787C>A	p.His263Asn	missense_variant	Exon 6 of 6	4		ENSP00000403363.1
EXTL2	ENST00000535414	c.*248C>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000444385.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.763C>A (p.H255N) alteration is located in exon 5 (coding exon 4) of the EXTL2 gene. This alteration results from a C to A substitution at nucleotide position 763, causing the histidine (H) at amino acid position 255 to be replaced by an asparagine (N). 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	0.094
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T;T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.7	M;M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.30	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.18
MutPred		0.52		Loss of methylation at K258 (P = 0.1138);Loss of methylation at K258 (P = 0.1138);.;
MVP		0.90
MPC		0.18
ClinPred		0.86	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-101339728;