chr3-50296917-A-T

Position:

• chr3-50296917-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001200016.2(NAA80):​c.547T>A​(p.Tyr183Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y183C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NAA80 NM_001200016.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.84

Genes affected

NAA80 (HGNC:30252): (N-alpha-acetyltransferase 80, NatH catalytic subunit) This gene encodes a member of the N-acetyltransferase family. N-acetyltransferases modify proteins by transferring acetyl groups from acetyl CoA to the N-termini of protein substrates. The encoded protein is a cytoplasmic N-acetyltransferase with a substrate specificity for proteins with an N-terminal methionine. This gene is located in the tumor suppressor gene region on chromosome 3p21.3 and the encoded protein may play a role in cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed. This gene overlaps and is on the same strand as hyaluronoglucosaminidase 3, and some transcripts of each gene share a portion of the first exon. [provided by RefSeq, Jan 2011]

HYAL3 (HGNC:5322): (hyaluronidase 3) This gene encodes a member of the hyaluronidase family. Hyaluronidases are endoglycosidase enzymes that degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. The regulated turnover of hyaluronan plays a critical role in many biological processes including cell proliferation, migration and differentiation. The encoded protein may also play an important role in sperm function. This gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression, and the expression of specific transcript variants may be indicative of tumor status. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and some isoforms may lack hyaluronidase activity. This gene overlaps and is on the same strand as N-acetyltransferase 6 (GCN5-related), and some transcripts of each gene share a portion of the first exon. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a mutagenesis_site In NAA80mut; abolished acetyltransferase activity; when associated with F-83, Q-148 and D-151. (size 0) in uniprot entity NAA80_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAA80	NM_001200016.2	c.547T>A	p.Tyr183Asn	missense_variant	2/2	ENST00000443094.3
HYAL3	NM_003549.4	c.-17-1298T>A		intron_variant		ENST00000336307.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAA80	ENST00000443094.3	c.547T>A	p.Tyr183Asn	missense_variant	2/2	1	NM_001200016.2	A2
HYAL3	ENST00000336307.6	c.-17-1298T>A		intron_variant		1	NM_003549.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000126 AC: 3 AN: 237632 Hom.: 0 AF XY: 0.00000766 AC XY: 1 AN XY: 130508

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000892

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457572 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000680

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 12, 2022

The c.613T>A (p.Y205N) alteration is located in exon 2 (coding exon 2) of the NAT6 gene. This alteration results from a T to A substitution at nucleotide position 613, causing the tyrosine (Y) at amino acid position 205 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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;.;D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.084	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PROVEAN	Pathogenic	-8.8	D;D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.95
MutPred		0.80		.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.62
MPC		0.95
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1174344957; hg19: chr3-50334348;