rs780016304

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-37522739-A-C
• chr20-37522739-A-G
• chr20-37522739-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001322802.2(NNAT):​c.221A>C​(p.Gln74Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/10 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. Q74L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NNAT NM_001322802.2 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10947335).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322802.2. 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>C	p.Arg76Arg	synonymous	Exon 3 of 3	NP_005377.1	Q16517-1
	BLCAP	NM_006698.4	MANE Select	c.-176-3389T>G		intron	N/A	NP_006689.1	P62952
	NNAT	NM_001322802.2		c.221A>C	p.Gln74Pro	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>C	p.Arg76Arg	synonymous	Exon 3 of 3	ENSP00000497164.1	Q16517-1
	NNAT	ENST00000346199.3	TSL:1	c.145A>C	p.Arg49Arg	synonymous	Exon 2 of 2	ENSP00000335497.2	Q16517-2
	BLCAP	ENST00000373537.7	TSL:1 MANE Select	c.-176-3389T>G		intron	N/A	ENSP00000362637.2	P62952

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 236972 AF XY: 0.00000776

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455328 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 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: 0.0000117 AC: 1 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 Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.77
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.11	T
PhyloP100		0.51
GERP RS		0.12
Mutation Taster		=99/1	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;