15-83257569-C-T

Position:

• chr15-83257569-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001717.4(BNC1):​c.2858G>A​(p.Arg953Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: BNC1 NM_001717.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

Genes affected

BNC1 (HGNC:1081): (basonuclin zinc finger protein 1) This gene encodes a zinc finger protein present in the basal cell layer of the epidermis and in hair follicles. It is also found in abundance in the germ cells of testis and ovary. This protein is thought to play a regulatory role in keratinocyte proliferation and it may also be a regulator for rRNA transcription. Disruption of this gene has been implicated in premature ovarian failure as well as testicular premature aging. [provided by RefSeq, Sep 2020]

ENSG00000259986 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3096074).
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BNC1	NM_001717.4	c.2858G>A	p.Arg953Gln	missense_variant	5/5	ENST00000345382.7	NP_001708.3
BNC1	NM_001301206.2	c.2837G>A	p.Arg946Gln	missense_variant	5/5		NP_001288135.1
BNC1	XM_011521893.2	c.2783G>A	p.Arg928Gln	missense_variant	5/5		XP_011520195.1
BNC1	XM_011521894.1	c.2504G>A	p.Arg835Gln	missense_variant	4/4		XP_011520196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BNC1	ENST00000345382.7	c.2858G>A	p.Arg953Gln	missense_variant	5/5	1	NM_001717.4	ENSP00000307041.2
BNC1	ENST00000569704.2	c.2837G>A	p.Arg946Gln	missense_variant	5/5	5		ENSP00000456727.1
ENSG00000259986	ENST00000565495.1	n.264+72501C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251272 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135792

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74238

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000721 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

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

Nov 09, 2024

The c.2858G>A (p.R953Q) alteration is located in exon 5 (coding exon 5) of the BNC1 gene. This alteration results from a G to A substitution at nucleotide position 2858, causing the arginine (R) at amino acid position 953 to be replaced by a glutamine (Q). 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.044	D;D
Polyphen		1.0	D;D
Vest4		0.49
MVP		0.30
MPC		0.47
ClinPred		0.13	T
GERP RS		5.9
Varity_R		0.34
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs150245231; hg19: chr15-83926321;