NM_052876.4:c.125A>G

Variant names:

• chr19-13135332-A-G
• rs2145623030
• NM_052876.4:c.125A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_052876.4(NACC1):​c.125A>G​(p.Lys42Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NACC1 NM_052876.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.48
• Publications: 0 publications found

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]

NACC1 Gene-Disease associations (from GenCC):

• NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-13135332-A-G is Benign according to our data. Variant chr19-13135332-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1389649.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052876.4. 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
	NACC1	NM_052876.4	MANE Select	c.125A>G	p.Lys42Arg	missense	Exon 2 of 6	NP_443108.1	Q96RE7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NACC1	ENST00000292431.5	TSL:1 MANE Select	c.125A>G	p.Lys42Arg	missense	Exon 2 of 6	ENSP00000292431.3	Q96RE7
	NACC1	ENST00000586171.3	TSL:5	c.125A>G	p.Lys42Arg	missense	Exon 3 of 7	ENSP00000467120.2	Q96RE7
	NACC1	ENST00000700232.1		c.125A>G	p.Lys42Arg	missense	Exon 2 of 6	ENSP00000514870.1	Q96RE7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.68	N
PhyloP100		7.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.34
Sift	Benign	0.25	T
Sift4G	Benign	0.69	T
Polyphen		0.32	B
Vest4		0.69
MutPred		0.63		Loss of methylation at K42 (P = 0.0285)
MVP		0.58
MPC		1.5
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.89
Mutation Taster		=65/35	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: rs2145623030; hg19: chr19-13246146;