Genetic Variant SMYD1:p.Asp75Asn (chr2-88084401-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_198274.4(SMYD1):c.223G>A(p.Asp75Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,608,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

SMYD1
NM_198274.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.54

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 129 AD gene.

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.223G>A	p.Asp75Asn	missense	Exon 2 of 10	NP_938015.1	Q8NB12
	SMYD1	NM_001330364.2		c.223G>A	p.Asp75Asn	missense	Exon 2 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.223G>A	p.Asp75Asn	missense	Exon 2 of 10	ENSP00000393453.2	Q8NB12
SMYD1	ENST00000965777.1		c.223G>A	p.Asp75Asn	missense	Exon 2 of 11	ENSP00000635836.1
SMYD1	ENST00000965776.1		c.319G>A	p.Asp107Asn	missense	Exon 3 of 11	ENSP00000635835.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251466

AF XY:

0.0000221

show subpopulations

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000886

AC:

129

AN:

1456594

Hom.:

Cov.:

AF XY:

0.0000815

AC XY:

AN XY:

723990

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39570

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85978

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000108

AC:

120

AN:

1107690

Other (OTH)

AF:

0.0000499

AC:

AN:

60120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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

AF:

0.0000263

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.040

PhyloP100

9.5

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.53

REVEL

Benign

0.12

Sift

Benign

0.11

Sift4G

Benign

0.19

Polyphen

0.17

Vest4

0.78

MutPred

0.60

Gain of MoRF binding (P = 0.0752)

MVP

0.27

MPC

0.099

ClinPred

0.51

GERP RS

5.6

Varity_R

0.19

gMVP

0.64

Mutation Taster

=66/34

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

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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