Genetic Variant SMYD1:p.Thr77Ile (chr2-88084408-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_198274.4(SMYD1):c.230C>T(p.Thr77Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,609,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SMYD1
NM_198274.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMYD1	NM_198274.4 link	c.230C>T	p.Thr77Ile	missense_variant	Exon 2 of 10	ENST00000419482.7	NP_938015.1	Q8NB12Q5HYE8
SMYD1	NM_001330364.2 link	c.230C>T	p.Thr77Ile	missense_variant	Exon 2 of 9		NP_001317293.1	E9PHG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMYD1	ENST00000419482.7 link	c.230C>T	p.Thr77Ile	missense_variant	Exon 2 of 10	1	NM_198274.4	ENSP00000393453.2	Q8NB12
SMYD1	ENST00000444564.2 link	c.230C>T	p.Thr77Ile	missense_variant	Exon 2 of 9	5		ENSP00000407888.2	E9PHG3
SMYD1	ENST00000438570.1 link	c.230C>T	p.Thr77Ile	missense_variant	Exon 2 of 3	2		ENSP00000387482.1	C9JUP3
SMYD1	ENST00000468008.1 link	n.260C>T		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251480

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1456948

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724250

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000217

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000547

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230C>T (p.T77I) alteration is located in exon 2 (coding exon 2) of the SMYD1 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the threonine (T) at amino acid position 77 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

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;.;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.82

MVP

0.36

MPC

0.39

ClinPred

0.98

GERP RS

5.6

Varity_R

0.72

gMVP

0.52

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over