2-73641102-T-C

Variant names:

• chr2-73641102-T-C
• rs867033767
• NM_003960.4:c.527A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003960.4(NAT8):​c.527A>G​(p.Asp176Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NAT8 NM_003960.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -6.50

Genes affected

NAT8 (HGNC:18069): (N-acetyltransferase 8 (putative)) This gene, isolated using the differential display method to detect tissue-specific genes, is specifically expressed in kidney and liver. The encoded protein shows amino acid sequence similarity to N-acetyltransferases. A similar protein in Xenopus affects cell adhesion and gastrulation movements, and may be localized in the secretory pathway. A highly similar paralog is found in a cluster with this gene. [provided by RefSeq, Sep 2008]

ALMS1P1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09731221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAT8	NM_003960.4	c.527A>G	p.Asp176Gly	missense_variant	Exon 2 of 2	ENST00000272425.4	NP_003951.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAT8	ENST00000272425.4	c.527A>G	p.Asp176Gly	missense_variant	Exon 2 of 2	1	NM_003960.4	ENSP00000272425.3
ALMS1P1	ENST00000652439.1	n.20T>C		non_coding_transcript_exon_variant	Exon 1 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461868 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000331

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

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.527A>G (p.D176G) alteration is located in exon 2 (coding exon 1) of the NAT8 gene. This alteration results from a A to G substitution at nucleotide position 527, causing the aspartic acid (D) at amino acid position 176 to be replaced by a glycine (G). 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	0.14
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.029
DANN	Benign	0.43
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.99	L
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.031
Sift	Benign	0.26	T
Sift4G	Benign	0.58	T
Polyphen		0.039	B
Vest4		0.12
MutPred		0.51		Loss of catalytic residue at D176 (P = 0.0318);
MVP		0.10
MPC		0.0046
ClinPred		0.83	D
GERP RS		-7.6
Varity_R		0.097
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs867033767; hg19: chr2-73868229;