2-88087867-C-G

Variant names:

• chr2-88087867-C-G
• rs780848017
• NM_198274.4:c.320C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198274.4(SMYD1):​c.320C>G​(p.Ala107Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0000042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMYD1 NM_198274.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27
• Publications: 5 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>G	p.Ala107Gly	missense	Exon 3 of 10	NP_938015.1	Q8NB12
	SMYD1	NM_001330364.2		c.320C>G	p.Ala107Gly	missense	Exon 3 of 9	NP_001317293.1	E9PHG3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMYD1	ENST00000419482.7	TSL:1 MANE Select	c.320C>G	p.Ala107Gly	missense	Exon 3 of 10	ENSP00000393453.2	Q8NB12
	SMYD1	ENST00000965777.1		c.320C>G	p.Ala107Gly	missense	Exon 3 of 11	ENSP00000635836.1
	SMYD1	ENST00000965776.1		c.416C>G	p.Ala139Gly	missense	Exon 4 of 11	ENSP00000635835.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000143 AC: 3 AN: 209688 AF XY: 0.00000882

Gnomad AFR exome AF: 0.0000726

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: 0.0000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000423 AC: 6 AN: 1419748 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702104

African (AFR) AF: 0.00 AC: 0 AN: 32724

American (AMR) AF: 0.00 AC: 0 AN: 40424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23880

East Asian (EAS) AF: 0.00 AC: 0 AN: 38322

South Asian (SAS) AF: 0.00 AC: 0 AN: 79906

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4484

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1090476

Other (OTH) AF: 0.00 AC: 0 AN: 58502

GnomAD4 genome Cov.: 31

ExAC AF: 0.000157 AC: 19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.70
MVP		0.42
MPC		0.41
ClinPred		0.84	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.55
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs780848017; hg19: chr2-88387386; COSMIC: COSV106580656;