NM_052928.3:c.2159C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_052928.3(SMYD4):​c.2159C>T​(p.Thr720Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SMYD4
NM_052928.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.554
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12410015).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMYD4NM_052928.3 linkc.2159C>T p.Thr720Ile missense_variant Exon 10 of 11 ENST00000305513.12 NP_443160.2 Q8IYR2
SMYD4XM_024450560.2 linkc.2159C>T p.Thr720Ile missense_variant Exon 10 of 11 XP_024306328.1
SMYD4XM_047435290.1 linkc.2159C>T p.Thr720Ile missense_variant Exon 10 of 10 XP_047291246.1
SMYD4XM_047435291.1 linkc.1847C>T p.Thr616Ile missense_variant Exon 9 of 10 XP_047291247.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMYD4ENST00000305513.12 linkc.2159C>T p.Thr720Ile missense_variant Exon 10 of 11 1 NM_052928.3 ENSP00000304360.7 Q8IYR2
SMYD4ENST00000491788.1 linkc.1571C>T p.Thr524Ile missense_variant Exon 6 of 6 2 ENSP00000460921.1 I3L428
SMYD4ENST00000476292.1 linkn.526C>T non_coding_transcript_exon_variant Exon 2 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251386
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.0000171
AC:
25
AN:
1461872
Hom.:
0
Cov.:
38
AF XY:
0.00000963
AC XY:
7
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.000223
AC:
34
AN:
152310
Hom.:
0
Cov.:
33
AF XY:
0.000269
AC XY:
20
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000625
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.000212
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2159C>T (p.T720I) alteration is located in exon 10 (coding exon 9) of the SMYD4 gene. This alteration results from a C to T substitution at nucleotide position 2159, causing the threonine (T) at amino acid position 720 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
9.6
DANN
Benign
0.97
DEOGEN2
Benign
0.0055
T;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.63
T;T
M_CAP
Benign
0.051
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.9
M;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.3
N;.
REVEL
Benign
0.031
Sift
Benign
0.13
T;.
Sift4G
Benign
0.23
T;T
Polyphen
0.35
B;.
Vest4
0.11
MVP
0.73
MPC
0.083
ClinPred
0.018
T
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.036
gMVP
0.073

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368740224; hg19: chr17-1686431; API