rs139849511

Variant names:

• chr1-109296338-G-A
• rs139849511
• NM_001010985.3:c.763C>T

Variant summary

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

The NM_001010985.3(MYBPHL):​c.763C>T​(p.Arg255*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,614,156 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00091 (2 hom.)
• Consequence: MYBPHL NM_001010985.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.516

Genes affected

MYBPHL (HGNC:30434): (myosin binding protein H like) This gene encodes a protein with two immunoglobulin superfamily domains and a fibronectin 3 domain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPHL	NM_001010985.3	c.763C>T	p.Arg255*	stop_gained	Exon 6 of 9	ENST00000357155.2	NP_001010985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPHL	ENST00000357155.2	c.763C>T	p.Arg255*	stop_gained	Exon 6 of 9	1	NM_001010985.3	ENSP00000349678.1
MYBPHL	ENST00000477962.1	n.150-1041C>T		intron_variant	Intron 1 of 3	1
MYBPHL	ENST00000489706.5	n.16C>T		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00128 AC: 321 AN: 251480 Hom.: 0 AF XY: 0.00125 AC XY: 170 AN XY: 135914

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000915 AC: 1337 AN: 1461882 Hom.: 2 Cov.: 36 AF XY: 0.000945 AC XY: 687 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00374

Gnomad4 NFE exome AF: 0.000910

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152274 Hom.: 0 Cov.: 31 AF XY: 0.000779 AC XY: 58 AN XY: 74464

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.000548

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Aug 12, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2022

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Brugada syndrome Uncertain:1

Mar 06, 2023

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Heterozygous variant NM_001010985:c.763C>T (p.Arg255*) in the MYBPHL gene was found on WES data in male proband (24 y.o., Caucasian) with Brugada-like ECG. Two additional rare candidate variants: NM_004415:c.5512C>T (p.Arg1838Cys) in the DSP gene (Class III of pathogenicity) and NM_001148:c.8899C>G (p.Pro2967Ala) in the ANK2 gene (Class III of pathogenicity) - were found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.001404 (Date of access 06-03-2023). Clinvar contains an entry for this variant (Variation ID: 994289). This variant has been reported in one study (PMID: 28778945) showing that the R255X is subject to NMD, a direct study of MYBPHL (PMID: 35533732) provides evidence of atrioventricular dysfunction following loss of Mybphl. Most in silico predictors show benign result of the protein change (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: PS3, BS1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.39	N
Vest4		0.18
GERP RS		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.45		Position offset: 32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139849511; hg19: chr1-109838960; COSMIC: COSV64063246;