4-177440340-A-T

Variant names:

• chr4-177440340-A-T
• NM_000027.4:c.214T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000027.4(AGA):​c.214T>A​(p.Ser72Thr) 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. 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. S72P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AGA NM_000027.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.15

Genes affected

AGA (HGNC:318): (aspartylglucosaminidase) This gene encodes a member of the N-terminal nucleophile (Ntn) hydrolase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta chains that comprise the mature enzyme. This enzyme is involved in the catabolism of N-linked oligosaccharides of glycoproteins. It cleaves asparagine from N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. Mutations in this gene are associated with the lysosomal storage disease aspartylglycosaminuria that results in progressive neurodegeneration. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is subject to proteolytic processing. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Glycosylasparaginase alpha chain (size 181) in uniprot entity ASPG_HUMAN there are 13 pathogenic changes around while only 5 benign (72%) in NM_000027.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-177440340-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.19165424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGA	NM_000027.4	c.214T>A	p.Ser72Thr	missense_variant	Exon 2 of 9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2	c.214T>A	p.Ser72Thr	missense_variant	Exon 2 of 9		NP_001165459.1
AGA	XM_047449722.1	c.214T>A	p.Ser72Thr	missense_variant	Exon 2 of 7		XP_047305678.1
AGA	NR_033655.2	n.276T>A		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7	c.214T>A	p.Ser72Thr	missense_variant	Exon 2 of 9	1	NM_000027.4	ENSP00000264595.2
AGA	ENST00000506853.5	n.248T>A		non_coding_transcript_exon_variant	Exon 2 of 6	2
AGA	ENST00000510955.5	n.248T>A		non_coding_transcript_exon_variant	Exon 2 of 4	2
AGA	ENST00000511231.1	n.248T>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.7
DANN	Benign	0.82
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-0.13	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.75		Loss of catalytic residue at S72 (P = 0.0342);
MVP		0.66
MPC		0.097
ClinPred		0.14	T
GERP RS		-0.29
Varity_R		0.24
gMVP		0.54

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: chr4-178361494;