chr14-23389065-G-T

Position:

• chr14-23389065-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002471.4(MYH6):​c.3979-10C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 123,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00032 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01427
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.25

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-23389065-G-T is Benign according to our data. Variant chr14-23389065-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 312856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23389065-G-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.3979-10C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.3979-10C>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 48 AN: 123556 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.000886

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000395

Gnomad OTH AF: 0.000575

GnomAD3 exomes AF: 0.000409 AC: 78 AN: 190566 Hom.: 0 AF XY: 0.000499 AC XY: 52 AN XY: 104112

Gnomad AFR exome AF: 0.0000881

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000948

Gnomad SAS exome AF: 0.000756

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000660

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000317 AC: 447 AN: 1408692 Hom.: 4 Cov.: 36 AF XY: 0.000343 AC XY: 240 AN XY: 699514

Gnomad4 AFR exome AF: 0.0000608

Gnomad4 AMR exome AF: 0.000417

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00112

Gnomad4 SAS exome AF: 0.000601

Gnomad4 FIN exome AF: 0.0000209

Gnomad4 NFE exome AF: 0.000290

Gnomad4 OTH exome AF: 0.000308

GnomAD4 genome AF: 0.000388 AC: 48 AN: 123664 Hom.: 0 Cov.: 30 AF XY: 0.000395 AC XY: 24 AN XY: 60728

Gnomad4 AFR AF: 0.000180

Gnomad4 AMR AF: 0.000902

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000587

Gnomad4 SAS AF: 0.000887

Gnomad4 FIN AF: 0.000112

Gnomad4 NFE AF: 0.000395

Gnomad4 OTH AF: 0.000568

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2023	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hypertrophic cardiomyopathy 14 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.6
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.13
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

Publications

LitVar

Other links and lift over

dbSNP: rs28730768; hg19: chr14-23858274;