17-4539966-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_014520.4(MYBBP1A):c.3436C>T(p.Arg1146Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,597,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1146H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: MYBBP1A NM_014520.4 missense, splice_region
• Scores: Splicing: ADA: 0.9884
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

Genes affected

MYBBP1A (HGNC:7546): (MYB binding protein 1a) This gene encodes a nucleolar transcriptional regulator that was first identified by its ability to bind specifically to the Myb proto-oncogene protein. The encoded protein is thought to play a role in many cellular processes including response to nucleolar stress, tumor suppression and synthesis of ribosomal DNA. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBBP1A	NM_014520.4	c.3436C>T	p.Arg1146Cys	missense_variant, splice_region_variant	26/26	ENST00000254718.9
MYBBP1A	NM_001105538.2	c.3436C>T	p.Arg1146Cys	missense_variant, splice_region_variant	26/27
MYBBP1A	XM_024450536.2	c.3299C>T	p.Ala1100Val	missense_variant, splice_region_variant	25/25
MYBBP1A	XM_011523616.3	c.2680C>T	p.Arg894Cys	missense_variant, splice_region_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBBP1A	ENST00000254718.9	c.3436C>T	p.Arg1146Cys	missense_variant, splice_region_variant	26/26	1	NM_014520.4	P2

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000238 AC: 56 AN: 235382 Hom.: 0 AF XY: 0.000209 AC XY: 27 AN XY: 129144

Gnomad AFR exome AF: 0.000553

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00105

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.0000851

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000156 AC: 226 AN: 1445594 Hom.: 0 Cov.: 36 AF XY: 0.000168 AC XY: 121 AN XY: 719356

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74446

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.000268

ESP6500AA AF: 0.000468 AC: 2

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000199 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

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

Jul 08, 2022

The c.3436C>T (p.R1146C) alteration is located in exon 26 (coding exon 26) of the MYBBP1A gene. This alteration results from a C to T substitution at nucleotide position 3436, causing the arginine (R) at amino acid position 1146 to be replaced by a cysteine (C). 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	Benign	0.25
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.74
MVP		0.34
ClinPred		0.22	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
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: rs145693408; hg19: chr17-4443261;