chr9-85962100-A-G

Position:

• chr9-85962100-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_024635.4(NAA35):​c.436A>G​(p.Met146Val) variant causes a missense change. The variant allele was found at a frequency of 0.000369 in 1,614,166 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: NAA35 NM_024635.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.14

Genes affected

NAA35 (HGNC:24340): (N-alpha-acetyltransferase 35, NatC auxiliary subunit) Involved in negative regulation of apoptotic process. Located in cytosol; nucleoplasm; and plasma membrane. Part of NatC complex. Colocalizes with polysome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NAA35
• BP4: Computational evidence support a benign effect (MetaRNN=0.07501307).
• BS2: High AC in GnomAd4 at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAA35	NM_024635.4	c.436A>G	p.Met146Val	missense_variant	6/23	ENST00000361671.10
NAA35	NM_001321881.2	c.436A>G	p.Met146Val	missense_variant	6/23
NAA35	NM_001321882.2	c.436A>G	p.Met146Val	missense_variant	6/23
NAA35	XM_005252127.5	c.436A>G	p.Met146Val	missense_variant	6/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAA35	ENST00000361671.10	c.436A>G	p.Met146Val	missense_variant	6/23	1	NM_024635.4	P1
NAA35	ENST00000376040.2	c.436A>G	p.Met146Val	missense_variant	6/12	2
NAA35	ENST00000416045.4	n.533A>G		non_coding_transcript_exon_variant	6/7	3

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152202 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000473 AC: 119 AN: 251450 Hom.: 0 AF XY: 0.000508 AC XY: 69 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.000747

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000348 AC: 508 AN: 1461846 Hom.: 2 Cov.: 30 AF XY: 0.000367 AC XY: 267 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.000365

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152320 Hom.: 2 Cov.: 31 AF XY: 0.000645 AC XY: 48 AN XY: 74472

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000567 Hom.: 1

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000568 AC: 69

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2021

The c.436A>G (p.M146V) alteration is located in exon 6 (coding exon 5) of the NAA35 gene. This alteration results from a A to G substitution at nucleotide position 436, causing the methionine (M) at amino acid position 146 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 146 of the NAA35 protein (p.Met146Val). This variant is present in population databases (rs149812553, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NAA35-related conditions. ClinVar contains an entry for this variant (Variation ID: 2160633). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T;.
Eigen	Benign	0.055
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.82	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.043	B;.
Vest4		0.65
MVP		0.27
MPC		0.88
ClinPred		0.038	T
GERP RS		5.9
Varity_R		0.38
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149812553; hg19: chr9-88577015;