chr17-47209535-C-T

Variant names:

• chr17-47209535-C-T
• rs780020430
• NM_002476.2:c.113C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002476.2(MYL4):​c.113C>T​(p.Ala38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A38G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MYL4 NM_002476.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 2 publications found

Genes affected

MYL4 (HGNC:7585): (myosin light chain 4) Myosin is a hexameric ATPase cellular motor protein. It is composed of two myosin heavy chains, two nonphosphorylatable myosin alkali light chains, and two phosphorylatable myosin regulatory light chains. This gene encodes a myosin alkali light chain that is found in embryonic muscle and adult atria. Two alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

MYL4 Gene-Disease associations (from GenCC):

• atrial fibrillation, familial, 18

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18211839).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002476.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL4	NM_002476.2	MANE Select	c.113C>T	p.Ala38Val	missense	Exon 1 of 7	NP_002467.1
	MYL4	NM_001002841.2		c.113C>T	p.Ala38Val	missense	Exon 2 of 8	NP_001002841.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL4	ENST00000393450.5	TSL:1 MANE Select	c.113C>T	p.Ala38Val	missense	Exon 1 of 7	ENSP00000377096.1
	MYL4	ENST00000354968.5	TSL:5	c.113C>T	p.Ala38Val	missense	Exon 2 of 8	ENSP00000347055.1
	MYL4	ENST00000572316.5	TSL:5	c.113C>T	p.Ala38Val	missense	Exon 2 of 8	ENSP00000461570.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251230 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 AF: 0.00000821 AC: 12 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.0098
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.077
Sift	Benign	0.058	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.13		Gain of methylation at K35 (P = 0.0909)
MVP		0.84
MPC		0.15
ClinPred		0.47	T
GERP RS		3.6
PromoterAI		-0.021	Neutral
Varity_R		0.074
gMVP		0.36
Mutation Taster		=81/19	polymorphism

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: rs780020430; hg19: chr17-45286901; COSMIC: COSV108884901;