6-135198935-A-G

Position:

• chr6-135198935-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001130173.2(MYB):​c.1594A>G​(p.Asn532Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYB NM_001130173.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

Genes affected

MYB (HGNC:7545): (MYB proto-oncogene, transcription factor) This gene encodes a protein with three HTH DNA-binding domains that functions as a transcription regulator. This protein plays an essential role in the regulation of hematopoiesis. This gene may be aberrently expressed or rearranged or undergo translocation in leukemias and lymphomas, and is considered to be an oncogene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

LOC105378011 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity MYB_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26471823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYB	NM_001130173.2	c.1594A>G	p.Asn532Asp	missense_variant	11/16	ENST00000341911.10
LOC105378011	XR_001744368.2	n.279-2935T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYB	ENST00000341911.10	c.1594A>G	p.Asn532Asp	missense_variant	11/16	1	NM_001130173.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458328 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725754

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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

Sep 26, 2023

The c.1594A>G (p.N532D) alteration is located in exon 11 (coding exon 11) of the MYB gene. This alteration results from a A to G substitution at nucleotide position 1594, causing the asparagine (N) at amino acid position 532 to be replaced by an aspartic acid (D). 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	0.095
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;T;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D;D;N;N;N;N;N;N;N
PrimateAI	Benign	0.47	T
Sift4G	Benign	0.46	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.43	B;P;.;.;B;B;.;.;.;.;.;.
Vest4		0.47
MutPred		0.58		Gain of glycosylation at S412 (P = 0.0877);.;Gain of glycosylation at S412 (P = 0.0877);Gain of glycosylation at S412 (P = 0.0877);.;Gain of glycosylation at S412 (P = 0.0877);Gain of glycosylation at S412 (P = 0.0877);.;.;.;Gain of glycosylation at S412 (P = 0.0877);.;
MVP		0.25
MPC		0.29
ClinPred		0.73	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.22

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: rs1391566299; hg19: chr6-135520073;