1-58660093-G-T

Variant names:

• chr1-58660093-G-T
• NM_001085487.3:c.2391C>A

Variant summary

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

The NM_001085487.3(MYSM1):​c.2391C>A​(p.Phe797Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYSM1 NM_001085487.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99

Genes affected

MYSM1 (HGNC:29401): (Myb like, SWIRM and MPN domains 1) Enables histone binding activity; peptidase activity; and transcription coactivator activity. Involved in several processes, including chromatin remodeling; monoubiquitinated histone H2A deubiquitination; and positive regulation of transcription by RNA polymerase II. Located in nucleolus and nucleoplasm. Part of protein-containing complex. Implicated in diabetic retinopathy. [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=0.18599781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYSM1	NM_001085487.3	c.2391C>A	p.Phe797Leu	missense_variant	Exon 20 of 20	ENST00000472487.6	NP_001078956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYSM1	ENST00000472487.6	c.2391C>A	p.Phe797Leu	missense_variant	Exon 20 of 20	1	NM_001085487.3	ENSP00000418734.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458690 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 797 of the MYSM1 protein (p.Phe797Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYSM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1400464). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYSM1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	0.027
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.14	T;T
Polyphen		0.60	P;.
Vest4		0.64
MutPred		0.33		Gain of helix (P = 0.0861);.;
MVP		0.55
MPC		0.33
ClinPred		0.95	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-59125765;