2-73220082-G-T

Position:

• chr2-73220082-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006062.3(SMYD5):​c.237G>T​(p.Lys79Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SMYD5 NM_006062.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.123

Genes affected

SMYD5 (HGNC:16258): (SMYD family member 5) Predicted to enable histone methyltransferase activity (H4-K20 specific). Involved in negative regulation of transposition and regulation of stem cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.09232986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMYD5	NM_006062.3	c.237G>T	p.Lys79Asn	missense_variant	3/13	ENST00000389501.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMYD5	ENST00000389501.9	c.237G>T	p.Lys79Asn	missense_variant	3/13	1	NM_006062.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727242

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000193 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.237G>T (p.K79N) alteration is located in exon 3 (coding exon 3) of the SMYD5 gene. This alteration results from a G to T substitution at nucleotide position 237, causing the lysine (K) at amino acid position 79 to be replaced by an asparagine (N). 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	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;.
MutationTaster	Benign	0.92	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.81	N;N
REVEL	Benign	0.053
Sift	Benign	0.067	T;T
Sift4G	Benign	0.095	T;T
Polyphen		0.0040	B;.
Vest4		0.21
MutPred		0.35		Loss of ubiquitination at K79 (P = 0.0098);.;
MVP		0.60
MPC		0.41
ClinPred		0.75	D
GERP RS		3.5
Varity_R		0.055
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs1024528920; hg19: chr2-73447210;