20-37521385-C-G

Position:

• chr20-37521385-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000373537.7(BLCAP):​c.-176-2035G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,786 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: 0.0000014 (0 hom.)
• Consequence: BLCAP ENST00000373537.7 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.227

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NNAT	NM_005386.4	c.54C>G	p.Ile18Met	missense_variant	1/3	ENST00000649451.1	NP_005377.1
BLCAP	NM_006698.4	c.-176-2035G>C		intron_variant		ENST00000373537.7	NP_006689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NNAT	ENST00000649451.1	c.54C>G	p.Ile18Met	missense_variant	1/3		NM_005386.4	ENSP00000497164	P4
BLCAP	ENST00000373537.7	c.-176-2035G>C		intron_variant		1	NM_006698.4	ENSP00000362637	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461786 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.54C>G (p.I18M) alteration is located in exon 1 (coding exon 1) of the NNAT gene. This alteration results from a C to G substitution at nucleotide position 54, causing the isoleucine (I) at amino acid position 18 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	.;T;.;T;.;.
Eigen	Benign	-0.0042
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.81	T;.;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.97	N;N;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N;N;.;.;.;.
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.
Polyphen		0.97	D;P;.;P;.;.
Vest4		0.79
MutPred		0.50		Loss of catalytic residue at L23 (P = 0.1042);Loss of catalytic residue at L23 (P = 0.1042);Loss of catalytic residue at L23 (P = 0.1042);Loss of catalytic residue at L23 (P = 0.1042);Loss of catalytic residue at L23 (P = 0.1042);Loss of catalytic residue at L23 (P = 0.1042);
MVP		0.27
MPC		1.7
ClinPred		1.0	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.49
gMVP		0.67

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: chr20-36149787;