Genetic Variant SMYD4:p.Arg707Gln (chr17-1783377-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_052928.3(SMYD4):c.2120G>A(p.Arg707Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,612,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R707W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

SMYD4
NM_052928.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.877

Publications

0 publications found

Variant links:

Genes affected

SMYD4 (HGNC:21067): (SET and MYND domain containing 4) Predicted to enable metal ion binding activity and methyltransferase activity. Involved in heart development. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SMYD4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027841568).

BP6

Variant 17-1783377-C-T is Benign according to our data. Variant chr17-1783377-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3446555.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052928.3. 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
	SMYD4	NM_052928.3	MANE Select	c.2120G>A	p.Arg707Gln	missense	Exon 9 of 11	NP_443160.2	Q8IYR2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMYD4	ENST00000305513.12	TSL:1 MANE Select	c.2120G>A	p.Arg707Gln	missense	Exon 9 of 11	ENSP00000304360.7	Q8IYR2
SMYD4	ENST00000954772.1		c.2120G>A	p.Arg707Gln	missense	Exon 9 of 11	ENSP00000624831.1
SMYD4	ENST00000954774.1		c.2120G>A	p.Arg707Gln	missense	Exon 9 of 11	ENSP00000624833.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.0000399

AC:

AN:

250434

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460070

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726350

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33426

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4504

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.0000591

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.063

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0043

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.67

M_CAP

Benign

0.027

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.4

PhyloP100

0.88

PrimateAI

Benign

0.24

PROVEAN

Benign

0.62

REVEL

Benign

0.093

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0080

Vest4

0.25

MVP

0.39

MPC

0.088

ClinPred

0.018

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.057

Mutation Taster

=91/9

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over