chr14-23389062-AGG-C

Variant names:

• chr14-23389060-GGA-GGC
• rs535111647
• NM_002471.4:c.3979-7T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002471.4(MYH6):​c.3979-7T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 115,738 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 26)
  • Exomes 𝑓: 0.00022 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Scores: Splicing: ADA: 0.01248
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.588
• Publications: 2 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]

MYH6 Gene-Disease associations (from GenCC):

• MYH-6 related congenital heart defects

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 14

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Keppen-Lubinsky syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrial septal defect 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-23389060-GGA-GGC is Benign according to our data. Variant chr14-23389062-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0013 (150/115738) while in subpopulation AFR AF = 0.00365 (142/38886). AF 95% confidence interval is 0.00316. There are 1 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 150 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.3979-7T>G		splice_region intron	N/A	NP_002462.2	P13533

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	ENST00000405093.9	TSL:5 MANE Select	c.3979-7T>G		splice_region intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4012-7T>G		splice_region intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-7T>G		splice_region intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 148 AN: 115624 Hom.: 1 Cov.: 26

Gnomad AFR AF: 0.00361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000532

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000427

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000301 AC: 42 AN: 139674 AF XY: 0.000223

Gnomad AFR exome AF: 0.00311

Gnomad AMR exome AF: 0.0000599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000223 AC: 236 AN: 1059466 Hom.: 2 Cov.: 27 AF XY: 0.000199 AC XY: 105 AN XY: 527996

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00386 AC: 117 AN: 30348

American (AMR) AF: 0.0000677 AC: 2 AN: 29558

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19390

East Asian (EAS) AF: 0.0000719 AC: 2 AN: 27798

South Asian (SAS) AF: 0.0000611 AC: 4 AN: 65516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4196

European-Non Finnish (NFE) AF: 0.000111 AC: 89 AN: 802494

Other (OTH) AF: 0.000465 AC: 21 AN: 45146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00130 AC: 150 AN: 115738 Hom.: 1 Cov.: 26 AF XY: 0.00146 AC XY: 83 AN XY: 56880

African (AFR) AF: 0.00365 AC: 142 AN: 38886

American (AMR) AF: 0.000532 AC: 6 AN: 11288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2598

East Asian (EAS) AF: 0.00 AC: 0 AN: 3034

South Asian (SAS) AF: 0.00 AC: 0 AN: 3434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.0000427 AC: 2 AN: 46890

Other (OTH) AF: 0.00 AC: 0 AN: 1590

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypertrophic cardiomyopathy 14 (1)
-	-	1	MYH6-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs535111647; hg19: chr14-23858269;