rs397516766

Variant names:

• chr14-23389061-GA-G
• rs397516766
• NM_002471.4:c.3979-7delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002471.4(MYH6):​c.3979-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 123,154 control chromosomes in the GnomAD database, including 30 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (30 hom., cov: 26)
  • Exomes 𝑓: 0.0028 (19 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:12
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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-GA-G is Benign according to our data. Variant chr14-23389061-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

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.3979-7delT		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.3979-7delT		splice_region intron	N/A	ENSP00000386041.3	P13533
	MYH6	ENST00000968262.1		c.4012-7delT		splice_region intron	N/A	ENSP00000638321.1
	MYH6	ENST00000968257.1		c.3979-7delT		splice_region intron	N/A	ENSP00000638316.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1562 AN: 123084 Hom.: 30 Cov.: 26

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000398

Gnomad SAS AF: 0.00141

Gnomad FIN AF: 0.000202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000289

Gnomad OTH AF: 0.00568

GnomAD2 exomes AF: 0.00315 AC: 583 AN: 184810 AF XY: 0.00231

Gnomad AFR exome AF: 0.0797

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000237

Gnomad OTH exome AF: 0.000439

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00280 AC: 3832 AN: 1366570 Hom.: 19 Cov.: 27 AF XY: 0.00250 AC XY: 1697 AN XY: 678616

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

African (AFR) AF: 0.0492 AC: 1553 AN: 31570

American (AMR) AF: 0.00207 AC: 89 AN: 42934

Ashkenazi Jewish (ASJ) AF: 0.00148 AC: 35 AN: 23662

East Asian (EAS) AF: 0.000333 AC: 13 AN: 39092

South Asian (SAS) AF: 0.000840 AC: 70 AN: 83378

European-Finnish (FIN) AF: 0.000292 AC: 14 AN: 47914

Middle Eastern (MID) AF: 0.00334 AC: 18 AN: 5384

European-Non Finnish (NFE) AF: 0.00176 AC: 1828 AN: 1036404

Other (OTH) AF: 0.00377 AC: 212 AN: 56232

⚠️ 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: 0.0127 AC: 1567 AN: 123154 Hom.: 30 Cov.: 26 AF XY: 0.0124 AC XY: 753 AN XY: 60486

African (AFR) AF: 0.0682 AC: 1483 AN: 21742

American (AMR) AF: 0.00327 AC: 46 AN: 14048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3086

East Asian (EAS) AF: 0.000399 AC: 2 AN: 5010

South Asian (SAS) AF: 0.00141 AC: 6 AN: 4242

European-Finnish (FIN) AF: 0.000202 AC: 2 AN: 9910

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

European-Non Finnish (NFE) AF: 0.000289 AC: 18 AN: 62274

Other (OTH) AF: 0.00561 AC: 10 AN: 1782

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0112

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Atrial septal defect (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic 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

Other links and lift over

dbSNP: rs397516766; hg19: chr14-23858270;