dbSNP rs780848017: SMYD1:p.Ala107Glu (chr2-88087867-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_198274.4(SMYD1):c.320C>A(p.Ala107Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A107V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SMYD1
NM_198274.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.27

Publications

0 publications found

Variant links:

Genes affected

SMYD1 (HGNC:20986): (SET and MYND domain containing 1) Predicted to enable histone-lysine N-methyltransferase activity. Involved in positive regulation of myoblast differentiation and positive regulation of myotube differentiation. Predicted to be located in cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SMYD1 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SMYD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.763

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198274.4. 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
	SMYD1	NM_198274.4	MANE Select	c.320C>A	p.Ala107Glu	missense	Exon 3 of 10	NP_938015.1	Q8NB12
	SMYD1	NM_001330364.2		c.320C>A	p.Ala107Glu	missense	Exon 3 of 9	NP_001317293.1	E9PHG3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMYD1	ENST00000419482.7	TSL:1 MANE Select	c.320C>A	p.Ala107Glu	missense	Exon 3 of 10	ENSP00000393453.2	Q8NB12
SMYD1	ENST00000965777.1		c.320C>A	p.Ala107Glu	missense	Exon 3 of 11	ENSP00000635836.1
SMYD1	ENST00000965776.1		c.416C>A	p.Ala139Glu	missense	Exon 4 of 11	ENSP00000635835.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1419748

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702104

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32724

American (AMR)

AF:

0.00

AC:

AN:

40424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23880

East Asian (EAS)

AF:

0.00

AC:

AN:

38322

South Asian (SAS)

AF:

0.00

AC:

AN:

79906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4484

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090476

Other (OTH)

AF:

0.0000171

AC:

AN:

58502

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.9

PhyloP100

2.3

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.27

Sift

Uncertain

0.024

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.84

MutPred

0.56

Gain of sheet (P = 0.0101)

MVP

0.49

MPC

0.46

ClinPred

0.99

GERP RS

4.8

Varity_R

0.92

gMVP

0.84

Mutation Taster

=79/21

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over