19-13135278-G-A

Position:

• chr19-13135278-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The ENST00000292431.5(NACC1):​c.71G>A​(p.Arg24Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: NACC1 ENST00000292431.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.06

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 Likely_pathogenic. Variant got 7 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, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACC1	NM_052876.4	c.71G>A	p.Arg24Gln	missense_variant	2/6	ENST00000292431.5	NP_443108.1
NACC1	XM_005259721.4	c.71G>A	p.Arg24Gln	missense_variant	3/7		XP_005259778.1
NACC1	XM_047438118.1	c.71G>A	p.Arg24Gln	missense_variant	2/6		XP_047294074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NACC1	ENST00000292431.5	c.71G>A	p.Arg24Gln	missense_variant	2/6	1	NM_052876.4	ENSP00000292431	P1
NACC1	ENST00000586171.3	c.71G>A	p.Arg24Gln	missense_variant	3/7	5		ENSP00000467120	P1
NACC1	ENST00000700232.1	c.71G>A	p.Arg24Gln	missense_variant	2/6			ENSP00000514870	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

NACC1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

The NACC1 c.71G>A variant is predicted to result in the amino acid substitution p.Arg24Gln. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant was observed de novo in two unrelated patients with neurodevelopmental anomalies (Internal data, PreventionGenetics). We interpret this variant as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2022

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	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.7	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	.;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.96
MutPred		0.83		Gain of catalytic residue at R24 (P = 0.1501);Gain of catalytic residue at R24 (P = 0.1501);
MVP		0.77
MPC		2.5
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.87

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: chr19-13246092; COSMIC: COSV52834248; COSMIC: COSV52834248;