19-13135293-A-G

Position:

• chr19-13135293-A-G

Variant summary

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

The ENST00000292431.5(NACC1):​c.86A>G​(p.Tyr29Cys) 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 (★). Synonymous variant affecting the same amino acid position (i.e. Y29Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NACC1 ENST00000292431.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41

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, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACC1	NM_052876.4	c.86A>G	p.Tyr29Cys	missense_variant	2/6	ENST00000292431.5	NP_443108.1
NACC1	XM_005259721.4	c.86A>G	p.Tyr29Cys	missense_variant	3/7		XP_005259778.1
NACC1	XM_047438118.1	c.86A>G	p.Tyr29Cys	missense_variant	2/6		XP_047294074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NACC1	ENST00000292431.5	c.86A>G	p.Tyr29Cys	missense_variant	2/6	1	NM_052876.4	ENSP00000292431	P1
NACC1	ENST00000586171.3	c.86A>G	p.Tyr29Cys	missense_variant	3/7	5		ENSP00000467120	P1
NACC1	ENST00000700232.1	c.86A>G	p.Tyr29Cys	missense_variant	2/6			ENSP00000514870	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 31, 2021

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. 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 (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 29 of the NACC1 protein (p.Tyr29Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.3	.;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	.;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.80		Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);
MVP		0.93
MPC		2.7
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.92

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: chr19-13246107;