rs145611185

Variant names:

• chr14-23388898-G-A
• rs145611185
• NM_002471.4:c.4136C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23388898-G-A
• chr14-23388898-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_002471.4(MYH6):​c.4136C>T​(p.Thr1379Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,613,670 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1379T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (2 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:14
• Conservation: PhyloP100: 9.65
• Publications: 14 publications found

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

MIR208A (HGNC:31585): (microRNA 208a) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• BP6: Variant 14-23388898-G-A is Benign according to our data. Variant chr14-23388898-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180425.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000912 (1333/1461448) while in subpopulation NFE AF = 0.00114 (1270/1112012). AF 95% confidence interval is 0.00109. There are 2 homozygotes in GnomAdExome4. There are 637 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 49 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002471.4. 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
	MYH6	NM_002471.4	MANE Select	c.4136C>T	p.Thr1379Met	missense	Exon 29 of 39	NP_002462.2	P13533
	MIR208A	NR_029595.1		n.-232C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.4136C>T	p.Thr1379Met	missense	Exon 29 of 39	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4169C>T	p.Thr1390Met	missense	Exon 29 of 39	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.4136C>T	p.Thr1379Met	missense	Exon 29 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000581 AC: 146 AN: 251472 AF XY: 0.000581

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000912 AC: 1333 AN: 1461448 Hom.: 2 Cov.: 32 AF XY: 0.000876 AC XY: 637 AN XY: 727034

African (AFR) AF: 0.000120 AC: 4 AN: 33470

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5396

European-Non Finnish (NFE) AF: 0.00114 AC: 1270 AN: 1112012

Other (OTH) AF: 0.000679 AC: 41 AN: 60368

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74376

African (AFR) AF: 0.000121 AC: 5 AN: 41464

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000547 Hom.: 0

Bravo AF: 0.000487

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.000981

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	1	2	not specified (3)
-	-	2	Hypertrophic cardiomyopathy 14 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	MYH6-related disorder (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.98
MPC		0.92
ClinPred		0.19	T
GERP RS		4.7
Varity_R		0.37
gMVP		0.61
Mutation Taster		=10/90	disease causing

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: rs145611185; hg19: chr14-23858107; COSMIC: COSV62452519; COSMIC: COSV62452519;