Genetic Variant NM_021073.4:c.1105-11_1105-10delGT (chr6-55759124-TAC-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_021073.4(BMP5):c.1105-11_1105-10delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 432,076 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 13)

Exomes 𝑓: 0.017 ( 5 hom. )

Consequence

BMP5
NM_021073.4 intron

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.73

Variant links:

Genes affected

BMP5 (HGNC:1072): (bone morphogenetic protein 5) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer, which plays a role in bone and cartilage development. Polymorphisms in this gene may be associated with osteoarthritis in human patients. This gene is differentially regulated in multiple human cancers. This gene encodes distinct protein isoforms that may be similarly proteolytically processed. [provided by RefSeq, Jul 2016]

BMP5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 6-55759124-TAC-T is Benign according to our data. Variant chr6-55759124-TAC-T is described in ClinVar as [Likely_benign]. Clinvar id is 3038228.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0169 (6401/377850) while in subpopulation EAS AF= 0.0325 (562/17314). AF 95% confidence interval is 0.0302. There are 5 homozygotes in gnomad4_exome. There are 3615 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
BMP5	NM_021073.4 link	c.1105-11_1105-10delGT	intron_variant	Intron 5 of 6	ENST00000370830.4	NP_066551.1	P22003-1M9VUD0A8K694
BMP5	NM_001329754.2 link	c.1104+1331_1104+1332delGT	intron_variant	Intron 5 of 5		NP_001316683.1	P22003-2A8K694
BMP5	NM_001329756.2 link	c.1028-3444_1028-3443delGT	intron_variant	Intron 4 of 4		NP_001316685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP5	ENST00000370830.4 link	c.1105-11_1105-10delGT		intron_variant	Intron 5 of 6	1	NM_021073.4	ENSP00000359866.3		P22003-1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

AN:

54196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00332

Gnomad ASJ

AF:

0.00221

Gnomad EAS

AF:

0.00225

Gnomad SAS

AF:

0.00136

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00694

AC:

1484

AN:

213682

Hom.:

AF XY:

0.00732

AC XY:

852

AN XY:

116414

show subpopulations

Gnomad AFR exome

AF:

0.00450

Gnomad AMR exome

AF:

0.00638

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.00715

Gnomad SAS exome

AF:

0.0130

Gnomad FIN exome

AF:

0.00475

Gnomad NFE exome

AF:

0.00547

Gnomad OTH exome

AF:

0.00843

GnomAD4 exome

AF:

0.0169

AC:

6401

AN:

377850

Hom.:

AF XY:

0.0169

AC XY:

3615

AN XY:

213658

show subpopulations

Gnomad4 AFR exome

AF:

0.0127

Gnomad4 AMR exome

AF:

0.00907

Gnomad4 ASJ exome

AF:

0.0207

Gnomad4 EAS exome

AF:

0.0325

Gnomad4 SAS exome

AF:

0.0131

Gnomad4 FIN exome

AF:

0.0148

Gnomad4 NFE exome

AF:

0.0180

Gnomad4 OTH exome

AF:

0.0206

GnomAD4 genome

AF:

0.00133

AC:

AN:

54226

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

23892

show subpopulations

Gnomad4 AFR

AF:

0.000580

Gnomad4 AMR

AF:

0.00331

Gnomad4 ASJ

AF:

0.00221

Gnomad4 EAS

AF:

0.00225

Gnomad4 SAS

AF:

0.00136

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

BMP5-related disorder

Benign:1

Mar 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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