NM_002471.4:c.3979-8_3979-7insT

Variant names:

• chr14-23389061-G-GA
• rs545343612
• NM_002471.4:c.3979-7dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002471.4(MYH6):​c.3979-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 123,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0024 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.588
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 14-23389061-G-GA is Benign according to our data. Variant chr14-23389061-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00197 (243/123168) while in subpopulation AMR AF = 0.00313 (44/14048). AF 95% confidence interval is 0.0024. There are 0 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 243 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.3979-7dupT		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.3979-7_3979-6insT		splice_region intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4012-7_4012-6insT		splice_region intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-7_3979-6insT		splice_region intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 243 AN: 123096 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.000324

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00271

Gnomad OTH AF: 0.00284

GnomAD2 exomes AF: 0.00189 AC: 349 AN: 184810 AF XY: 0.00180

Gnomad AFR exome AF: 0.000895

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000723

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00220

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00239 AC: 3275 AN: 1367802 Hom.: 1 Cov.: 27 AF XY: 0.00235 AC XY: 1597 AN XY: 679218

African (AFR) AF: 0.000379 AC: 12 AN: 31658

American (AMR) AF: 0.00373 AC: 160 AN: 42940

Ashkenazi Jewish (ASJ) AF: 0.0000422 AC: 1 AN: 23686

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39112

South Asian (SAS) AF: 0.000132 AC: 11 AN: 83404

European-Finnish (FIN) AF: 0.0000835 AC: 4 AN: 47930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5386

European-Non Finnish (NFE) AF: 0.00290 AC: 3006 AN: 1037408

Other (OTH) AF: 0.00142 AC: 80 AN: 56278

GnomAD4 genome AF: 0.00197 AC: 243 AN: 123168 Hom.: 0 Cov.: 26 AF XY: 0.00188 AC XY: 114 AN XY: 60500

African (AFR) AF: 0.00101 AC: 22 AN: 21754

American (AMR) AF: 0.00313 AC: 44 AN: 14048

Ashkenazi Jewish (ASJ) AF: 0.000324 AC: 1 AN: 3086

East Asian (EAS) AF: 0.00 AC: 0 AN: 5010

South Asian (SAS) AF: 0.00 AC: 0 AN: 4242

European-Finnish (FIN) AF: 0.000202 AC: 2 AN: 9912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.00271 AC: 169 AN: 62274

Other (OTH) AF: 0.00281 AC: 5 AN: 1782

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00206

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 14 (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
SpliceAI score (max)		0.010		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: rs545343612; hg19: chr14-23858270;