chr8-18223689-A-C

Variant names:

• chr8-18223689-A-C
• rs8190865
• NM_000662.8:c.*769A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000662.8(NAT1):​c.*769A>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 129,410 control chromosomes in the GnomAD database, including 38 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (38 hom., cov: 31)
  • Exomes 𝑓: 0.00066 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAT1 NM_000662.8 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.406
• Publications: 0 publications found

Genes affected

NAT1 (HGNC:7645): (N-acetyltransferase 1) This gene is one of two arylamine N-acetyltransferase (NAT) genes in the human genome, and is orthologous to the mouse and rat Nat2 genes. The enzyme encoded by this gene catalyzes the transfer of an acetyl group from acetyl-CoA to various arylamine and hydrazine substrates. This enzyme helps metabolize drugs and other xenobiotics, and functions in folate catabolism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000662.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT1	NM_000662.8	MANE Select	c.*769A>C		splice_region	Exon 3 of 3	NP_000653.3
	NAT1	NM_000662.8	MANE Select	c.*769A>C		3_prime_UTR	Exon 3 of 3	NP_000653.3
	NAT1	NM_001160175.4		c.*769A>C		splice_region	Exon 5 of 5	NP_001153647.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT1	ENST00000307719.9	TSL:1 MANE Select	c.*769A>C		splice_region	Exon 3 of 3	ENSP00000307218.4
	NAT1	ENST00000518029.5	TSL:1	c.*769A>C		splice_region	Exon 4 of 4	ENSP00000428270.1
	NAT1	ENST00000307719.9	TSL:1 MANE Select	c.*769A>C		3_prime_UTR	Exon 3 of 3	ENSP00000307218.4

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1590 AN: 129282 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00311

Gnomad ASJ AF: 0.000359

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000260

Gnomad FIN AF: 0.000139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.00723

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000665 AC: 5 AN: 7520 Hom.: 0 Cov.: 0 AF XY: 0.000554 AC XY: 2 AN XY: 3612

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.000676 AC: 5 AN: 7400

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62

Other (OTH) AF: 0.00 AC: 0 AN: 50

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0123 AC: 1586 AN: 129410 Hom.: 38 Cov.: 31 AF XY: 0.0117 AC XY: 735 AN XY: 62906

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0396 AC: 1508 AN: 38044

American (AMR) AF: 0.00311 AC: 42 AN: 13512

Ashkenazi Jewish (ASJ) AF: 0.000359 AC: 1 AN: 2782

East Asian (EAS) AF: 0.00 AC: 0 AN: 5016

South Asian (SAS) AF: 0.000261 AC: 1 AN: 3838

European-Finnish (FIN) AF: 0.000139 AC: 1 AN: 7216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000356 AC: 20 AN: 56224

Other (OTH) AF: 0.00715 AC: 13 AN: 1818

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0385 Hom.: 51

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.8
DANN	Benign	0.42
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs8190865; hg19: chr8-18081198;