chr2-73641267-A-G

Variant names:

• chr2-73641267-A-G
• rs62000430
• NM_003960.4:c.362T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003960.4(NAT8):​c.362T>C​(p.Met121Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,614,100 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M121I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (69 hom.)
• Consequence: NAT8 NM_003960.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0690
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0083195865).
• BP6: Variant 2-73641267-A-G is Benign according to our data. Variant chr2-73641267-A-G is described in ClinVar as Benign. ClinVar VariationId is 720099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003960.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT8	NM_003960.4	MANE Select	c.362T>C	p.Met121Thr	missense	Exon 2 of 2	NP_003951.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAT8	ENST00000272425.4	TSL:1 MANE Select	c.362T>C	p.Met121Thr	missense	Exon 2 of 2	ENSP00000272425.3	Q9UHE5
	NAT8	ENST00000852385.1		c.362T>C	p.Met121Thr	missense	Exon 2 of 2	ENSP00000522444.1
	NAT8	ENST00000852386.1		c.362T>C	p.Met121Thr	missense	Exon 2 of 2	ENSP00000522445.1

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 856 AN: 152112 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00492

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00875

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00716 AC: 1801 AN: 251422 AF XY: 0.00723

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00753 AC: 11007 AN: 1461870 Hom.: 69 Cov.: 32 AF XY: 0.00762 AC XY: 5539 AN XY: 727238

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00322 AC: 144 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00543 AC: 142 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0104 AC: 897 AN: 86258

European-Finnish (FIN) AF: 0.00487 AC: 260 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00826 AC: 9189 AN: 1112010

Other (OTH) AF: 0.00556 AC: 336 AN: 60396

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152230 Hom.: 6 Cov.: 32 AF XY: 0.00528 AC XY: 393 AN XY: 74442

African (AFR) AF: 0.00140 AC: 58 AN: 41538

American (AMR) AF: 0.00491 AC: 75 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4824

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00875 AC: 595 AN: 68012

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00732 Hom.: 14

Bravo AF: 0.00519

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.00774 AC: 940

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.00796

EpiControl AF: 0.00771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.49
DANN	Benign	0.30
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.069
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.039
Sift	Benign	0.57	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.14
MPC		0.0048
ClinPred		0.0033	T
GERP RS		-1.9
Varity_R		0.059
gMVP		0.56
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs62000430; hg19: chr2-73868394; COSMIC: COSV55542143; COSMIC: COSV55542143;