rs72680532

Positions:

• chr14-53951825-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001202.6(BMP4):​c.370+28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,597,926 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (14 hom., cov: 33)
  • Exomes 𝑓: 0.011 (86 hom.)
• Consequence: BMP4 NM_001202.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.703

Genes affected

BMP4 (HGNC:1071): (bone morphogenetic protein 4) 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. This protein regulates heart development and adipogenesis. Mutations in this gene are associated with orofacial cleft and microphthalmia in human patients. The encoded protein may also be involved in the pathology of multiple cardiovascular diseases and human cancers. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037618577).
• BP6: Variant 14-53951825-C-T is Benign according to our data. Variant chr14-53951825-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-53951825-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00838 (1276/152322) while in subpopulation NFE AF= 0.0118 (805/68032). AF 95% confidence interval is 0.0112. There are 14 homozygotes in gnomad4. There are 649 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1276 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP4	NM_001202.6	c.370+28G>A		intron_variant		ENST00000245451.9	NP_001193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP4	ENST00000245451.9	c.370+28G>A		intron_variant		1	NM_001202.6	ENSP00000245451	P1

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1277 AN: 152204 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00773 AC: 1829 AN: 236534 Hom.: 15 AF XY: 0.00787 AC XY: 1018 AN XY: 129348

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00302

Gnomad ASJ exome AF: 0.00483

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00706

GnomAD4 exome AF: 0.0112 AC: 16130 AN: 1445604 Hom.: 86 Cov.: 32 AF XY: 0.0108 AC XY: 7745 AN XY: 719400

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000929

Gnomad4 FIN exome AF: 0.0237

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.00838 AC: 1276 AN: 152322 Hom.: 14 Cov.: 33 AF XY: 0.00871 AC XY: 649 AN XY: 74502

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0243

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0106 Hom.: 5

Bravo AF: 0.00644

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.00829 AC: 1001

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BMP4: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 20, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 12, 2018

- -

Microphthalmia with brain and digit anomalies;C2677434:Orofacial cleft 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.84
FATHMM_MKL	Benign	0.36	N
MetaRNN	Benign	0.0038	T
MutationTaster	Benign	1.0	N;N;N;N
MVP		0.75
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs72680532; hg19: chr14-54418543;