19-13135341-G-A

Position:

• chr19-13135341-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_052876.4(NACC1):​c.134G>A​(p.Arg45Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,334 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NACC1 NM_052876.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.90

Genes affected

NACC1 (HGNC:20967): (nucleus accumbens associated 1) This gene encodes a member of the BTB/POZ protein family. BTB/POZ proteins are involved in several cellular processes including proliferation, apoptosis and transcription regulation. The encoded protein is a transcriptional repressor that plays a role in stem cell self-renewal and pluripotency maintenance. The encoded protein also suppresses transcription of the candidate tumor suppressor Gadd45GIP1, and expression of this gene may play a role in the progression of multiple types of cancer. A pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NACC1. . Gene score misZ 4.1668 (greater than the threshold 3.09). Trascript score misZ 3.946 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACC1	NM_052876.4	c.134G>A	p.Arg45Gln	missense_variant	2/6	ENST00000292431.5	NP_443108.1
NACC1	XM_005259721.4	c.134G>A	p.Arg45Gln	missense_variant	3/7		XP_005259778.1
NACC1	XM_047438118.1	c.134G>A	p.Arg45Gln	missense_variant	2/6		XP_047294074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NACC1	ENST00000292431.5	c.134G>A	p.Arg45Gln	missense_variant	2/6	1	NM_052876.4	ENSP00000292431.3
NACC1	ENST00000586171.3	c.134G>A	p.Arg45Gln	missense_variant	3/7	5		ENSP00000467120.2
NACC1	ENST00000700232.1	c.134G>A	p.Arg45Gln	missense_variant	2/6			ENSP00000514870.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461334 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 09, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with NACC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 45 of the NACC1 protein (p.Arg45Gln). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	.;D
REVEL	Uncertain	0.51
Sift	Benign	0.034	.;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.92
MutPred		0.78		Gain of catalytic residue at R45 (P = 0.0352);Gain of catalytic residue at R45 (P = 0.0352);
MVP		0.76
MPC		2.1
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.56
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13246155; COSMIC: COSV52834197; COSMIC: COSV52834197;