6-45422583-A-T

Position:

chr6-45422583-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4BP6_ModerateBS1BS2

The ENST00000359524.7(RUNX2):c.7A>T(p.Ile3Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,505,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

RUNX2
ENST00000359524.7 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.32

Variant links:

Genes affected

RUNX2 (HGNC:10472): (RUNX family transcription factor 2) This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Two regions of potential trinucleotide repeat expansions are present in the N-terminal region of the encoded protein, and these and other mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing. [provided by RefSeq, Jul 2016]

RUNX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3427636).

BP6

Variant 6-45422583-A-T is Benign according to our data. Variant chr6-45422583-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1902600.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000135 (19/141054) while in subpopulation AFR AF= 0.000474 (18/37936). AF 95% confidence interval is 0.000306. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RUNX2	NM_001024630.4 linkuse as main transcript	c.59-10A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000647337.2
RUNX2	NM_001369405.1 linkuse as main transcript	c.7A>T	p.Ile3Phe	missense_variant	1/7
RUNX2	NM_001278478.2 linkuse as main transcript	c.7A>T	p.Ile3Phe	missense_variant	1/6
RUNX2	NM_001015051.4 linkuse as main transcript	c.59-10A>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX2	ENST00000647337.2 linkuse as main transcript	c.59-10A>T		splice_polypyrimidine_tract_variant, intron_variant			NM_001024630.4	P4	Q13950-1

Frequencies

GnomAD3 genomes

AF:

0.000135

AC:

AN:

140998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000476

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000756

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000339

AC:

AN:

235840

Hom.:

AF XY:

0.0000309

AC XY:

AN XY:

129290

show subpopulations

Gnomad AFR exome

AF:

0.000502

Gnomad AMR exome

AF:

0.0000314

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000733

AC:

AN:

1364538

Hom.:

Cov.:

AF XY:

0.00000442

AC XY:

AN XY:

678930

show subpopulations

Gnomad4 AFR exome

AF:

0.000265

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:

0.00

Gnomad4 OTH exome

AF:

0.0000370

GnomAD4 genome

AF:

0.000135

AC:

AN:

141054

Hom.:

Cov.:

AF XY:

0.0000885

AC XY:

AN XY:

67798

show subpopulations

Gnomad4 AFR

AF:

0.000474

Gnomad4 AMR

AF:

0.0000755

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ESP6500AA

AF:

0.000788

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000586

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

0.084

MutationTaster

Benign

1.0

D;D;D;D;D;D;N;N

PROVEAN

Benign

-0.64

N;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.28

B;.

Vest4

0.66

MVP

0.55

ClinPred

0.11

GERP RS

1.4

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over