20-37522739-A-G

Variant names:

• chr20-37522739-A-G
• rs780016304
• NM_005386.4:c.226A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005386.4(NNAT):​c.226A>G​(p.Arg76Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NNAT NM_005386.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508
• Publications: 0 publications found

Genes affected

NNAT (HGNC:7860): (neuronatin) The protein encoded by this gene is a proteolipid that may be involved in the regulation of ion channels during brain development. The encoded protein may also play a role in forming and maintaining the structure of the nervous system. This gene is found within an intron of another gene, bladder cancer associated protein, but on the opposite strand. This gene is imprinted and is expressed only from the paternal allele. [provided by RefSeq, Apr 2016]

BLCAP (HGNC:1055): (BLCAP apoptosis inducing factor) This gene encodes a protein that reduces cell growth by stimulating apoptosis. Alternative splicing and the use of alternative promoters result in multiple transcript variants encoding the same protein. This gene is imprinted in brain where different transcript variants are expressed from each parental allele. Transcript variants initiating from the upstream promoter are expressed preferentially from the maternal allele, while transcript variants initiating downstream of the interspersed NNAT gene (GeneID:4826) are expressed from the paternal allele. Transcripts at this locus may also undergo A to I editing, resulting in amino acid changes at three positions in the N-terminus of the protein. [provided by RefSeq, Nov 2015]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28549564).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005386.4. 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
	NNAT	NM_005386.4	MANE Select	c.226A>G	p.Arg76Gly	missense	Exon 3 of 3	NP_005377.1	Q16517-1
	BLCAP	NM_006698.4	MANE Select	c.-176-3389T>C		intron	N/A	NP_006689.1	P62952
	NNAT	NM_001322802.2		c.221A>G	p.Gln74Arg	missense	Exon 3 of 3	NP_001309731.1	A0A3B3ITN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NNAT	ENST00000649451.1	MANE Select	c.226A>G	p.Arg76Gly	missense	Exon 3 of 3	ENSP00000497164.1	Q16517-1
	NNAT	ENST00000346199.3	TSL:1	c.145A>G	p.Arg49Gly	missense	Exon 2 of 2	ENSP00000335497.2	Q16517-2
	BLCAP	ENST00000373537.7	TSL:1 MANE Select	c.-176-3389T>C		intron	N/A	ENSP00000362637.2	P62952

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455328 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723376

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.00 AC: 0 AN: 85330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109642

Other (OTH) AF: 0.00 AC: 0 AN: 59948

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.29	T
PhyloP100		0.51
ClinPred		0.82	D
GERP RS		0.12
Varity_R		0.22
Mutation Taster		=91/9	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: rs780016304; hg19: chr20-36151141;