1-100874313-A-G

Variant names:

• chr1-100874313-A-G
• NM_001033025.3:c.622T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001033025.3(EXTL2):​c.622T>C​(p.Tyr208His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: EXTL2 NM_001033025.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXTL2	NM_001033025.3	c.622T>C	p.Tyr208His	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.622T>C	p.Tyr208His	missense_variant	Exon 5 of 5	1	NM_001033025.3	ENSP00000359132.3
EXTL2	ENST00000370113.7	c.622T>C	p.Tyr208His	missense_variant	Exon 5 of 5	1		ENSP00000359131.3
EXTL2	ENST00000450240.2	c.646T>C	p.Tyr216His	missense_variant	Exon 6 of 6	4		ENSP00000403363.1
EXTL2	ENST00000535414	c.*107T>C		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

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.622T>C (p.Y208H) alteration is located in exon 5 (coding exon 4) of the EXTL2 gene. This alteration results from a T to C substitution at nucleotide position 622, causing the tyrosine (Y) at amino acid position 208 to be replaced by a histidine (H). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.4	M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.78
MutPred		0.80		Loss of phosphorylation at Y208 (P = 0.0197);Loss of phosphorylation at Y208 (P = 0.0197);.;
MVP		0.93
MPC		0.77
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.58
gMVP		0.79

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: chr1-101339869;