1-109296296-C-T

Variant names:

• chr1-109296296-C-T
• rs629001
• NM_001010985.3:c.805G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001010985.3(MYBPHL):​c.805G>A​(p.Asp269Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.925 in 1,613,934 control chromosomes in the GnomAD database, including 691,924 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58961 hom., cov: 30)
  • Exomes 𝑓: 0.93 (632963 hom.)
• Consequence: MYBPHL NM_001010985.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.96
• Publications: 40 publications found

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]

MYBPHL Gene-Disease associations (from GenCC):

• familial dilated cardiomyopathy

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.7328716E-7).
• BP6: Variant 1-109296296-C-T is Benign according to our data. Variant chr1-109296296-C-T is described in ClinVar as Benign. ClinVar VariationId is 1253160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010985.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPHL	NM_001010985.3	MANE Select	c.805G>A	p.Asp269Asn	missense	Exon 6 of 9	NP_001010985.2	A2RUH7-1
	MYBPHL	NM_001265613.2		c.736G>A	p.Asp246Asn	missense	Exon 6 of 9	NP_001252542.1	A2RUH7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPHL	ENST00000357155.2	TSL:1 MANE Select	c.805G>A	p.Asp269Asn	missense	Exon 6 of 9	ENSP00000349678.1	A2RUH7-1
	MYBPHL	ENST00000477962.1	TSL:1	n.150-999G>A		intron	N/A
	MYBPHL	ENST00000968920.1		c.985G>A	p.Asp329Asn	missense	Exon 6 of 9	ENSP00000638979.1

Frequencies

GnomAD3 genomes AF: 0.874 AC: 132861 AN: 151964 Hom.: 58931 Cov.: 30

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.905

Gnomad AMR AF: 0.939

Gnomad ASJ AF: 0.937

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.943

Gnomad FIN AF: 0.959

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.891

GnomAD2 exomes AF: 0.928 AC: 233468 AN: 251482 AF XY: 0.932

Gnomad AFR exome AF: 0.694

Gnomad AMR exome AF: 0.959

Gnomad ASJ exome AF: 0.933

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.960

Gnomad NFE exome AF: 0.929

Gnomad OTH exome AF: 0.930

GnomAD4 exome AF: 0.930 AC: 1359175 AN: 1461852 Hom.: 632963 Cov.: 59 AF XY: 0.931 AC XY: 677252 AN XY: 727236

African (AFR) AF: 0.698 AC: 23379 AN: 33474

American (AMR) AF: 0.955 AC: 42723 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 24378 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39692 AN: 39700

South Asian (SAS) AF: 0.950 AC: 81923 AN: 86256

European-Finnish (FIN) AF: 0.960 AC: 51302 AN: 53420

Middle Eastern (MID) AF: 0.934 AC: 5386 AN: 5764

European-Non Finnish (NFE) AF: 0.930 AC: 1034461 AN: 1111986

Other (OTH) AF: 0.926 AC: 55931 AN: 60392

GnomAD4 genome AF: 0.874 AC: 132946 AN: 152082 Hom.: 58961 Cov.: 30 AF XY: 0.879 AC XY: 65333 AN XY: 74352

African (AFR) AF: 0.702 AC: 29065 AN: 41416

American (AMR) AF: 0.939 AC: 14361 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.937 AC: 3252 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5163 AN: 5164

South Asian (SAS) AF: 0.943 AC: 4529 AN: 4804

European-Finnish (FIN) AF: 0.959 AC: 10171 AN: 10604

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63424 AN: 68016

Other (OTH) AF: 0.893 AC: 1887 AN: 2114

Alfa AF: 0.912 Hom.: 188459

Bravo AF: 0.865

TwinsUK AF: 0.923 AC: 3423

ALSPAC AF: 0.933 AC: 3596

ESP6500AA AF: 0.714 AC: 3148

ESP6500EA AF: 0.935 AC: 8037

ExAC AF: 0.922 AC: 111932

Asia WGS AF: 0.947 AC: 3293 AN: 3478

EpiCase AF: 0.936

EpiControl AF: 0.935

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	6.7e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.64	T
Sift4G	Benign	0.28	T
Polyphen		0.010	B
Vest4		0.13
MPC		0.22
ClinPred		0.014	T
GERP RS		3.3
Varity_R		0.079
gMVP		0.22
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs629001; hg19: chr1-109838918; COSMIC: COSV107453711;