NM_005386.4:c.226A>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005386.4(NNAT):​c.226A>T​(p.Arg76Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,455,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: NNAT NM_005386.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Arg76Trp	missense	Exon 3 of 3	NP_005377.1	Q16517-1
	BLCAP	NM_006698.4	MANE Select	c.-176-3389T>A		intron	N/A	NP_006689.1	P62952
	NNAT	NM_001322802.2		c.221A>T	p.Gln74Leu	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>T	p.Arg76Trp	missense	Exon 3 of 3	ENSP00000497164.1	Q16517-1
	NNAT	ENST00000346199.3	TSL:1	c.145A>T	p.Arg49Trp	missense	Exon 2 of 2	ENSP00000335497.2	Q16517-2
	BLCAP	ENST00000373537.7	TSL:1 MANE Select	c.-176-3389T>A		intron	N/A	ENSP00000362637.2	P62952

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 236972 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000268 AC: 39 AN: 1455328 Hom.: 0 Cov.: 31 AF XY: 0.0000276 AC XY: 20 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: 0.0000351 AC: 39 AN: 1109642

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.000187 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.20	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.47	T
PhyloP100		0.51
ClinPred		0.98	D
GERP RS		0.12
Varity_R		0.28
Mutation Taster		=95/5	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;