chr1-58660011-C-T

Variant names:

• chr1-58660011-C-T
• rs232777
• NM_001085487.3:c.2473G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001085487.3(MYSM1):​c.2473G>A​(p.Glu825Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,575,666 control chromosomes in the GnomAD database, including 35,092 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E825E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6197 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28895 hom.)
• Consequence: MYSM1 NM_001085487.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.137
• Publications: 24 publications found

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]

MYSM1 Gene-Disease associations (from GenCC):

• bone marrow failure syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen

ENSG00000283445 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013670623).
• BP6: Variant 1-58660011-C-T is Benign according to our data. Variant chr1-58660011-C-T is described in ClinVar as Benign. ClinVar VariationId is 1169778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085487.3. 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
	MYSM1	NM_001085487.3	MANE Select	c.2473G>A	p.Glu825Lys	missense	Exon 20 of 20	NP_001078956.1	Q5VVJ2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYSM1	ENST00000472487.6	TSL:1 MANE Select	c.2473G>A	p.Glu825Lys	missense	Exon 20 of 20	ENSP00000418734.1	Q5VVJ2-1
	MYSM1	ENST00000401044.7	TSL:1	n.2318G>A		non_coding_transcript_exon	Exon 17 of 17
	MYSM1	ENST00000493821.6	TSL:1	n.2522G>A		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40489 AN: 151764 Hom.: 6178 Cov.: 32

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.242

GnomAD2 exomes AF: 0.233 AC: 53391 AN: 228820 AF XY: 0.230

Gnomad AFR exome AF: 0.409

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.192 AC: 273326 AN: 1423784 Hom.: 28895 Cov.: 28 AF XY: 0.194 AC XY: 137183 AN XY: 708410

African (AFR) AF: 0.412 AC: 12866 AN: 31206

American (AMR) AF: 0.260 AC: 10196 AN: 39182

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4579 AN: 24892

East Asian (EAS) AF: 0.209 AC: 8134 AN: 38950

South Asian (SAS) AF: 0.259 AC: 20865 AN: 80634

European-Finnish (FIN) AF: 0.338 AC: 17780 AN: 52544

Middle Eastern (MID) AF: 0.164 AC: 916 AN: 5600

European-Non Finnish (NFE) AF: 0.170 AC: 185319 AN: 1092190

Other (OTH) AF: 0.216 AC: 12671 AN: 58586

GnomAD4 genome AF: 0.267 AC: 40556 AN: 151882 Hom.: 6197 Cov.: 32 AF XY: 0.274 AC XY: 20309 AN XY: 74238

African (AFR) AF: 0.409 AC: 16951 AN: 41414

American (AMR) AF: 0.243 AC: 3704 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 617 AN: 3466

East Asian (EAS) AF: 0.238 AC: 1231 AN: 5176

South Asian (SAS) AF: 0.283 AC: 1364 AN: 4818

European-Finnish (FIN) AF: 0.357 AC: 3760 AN: 10532

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12320 AN: 67946

Other (OTH) AF: 0.242 AC: 510 AN: 2104

Alfa AF: 0.205 Hom.: 12234

Bravo AF: 0.262

TwinsUK AF: 0.168 AC: 622

ALSPAC AF: 0.167 AC: 645

ESP6500AA AF: 0.389 AC: 1406

ESP6500EA AF: 0.171 AC: 1396

ExAC AF: 0.235 AC: 28425

Asia WGS AF: 0.279 AC: 969 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.14
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.072
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.13	T
Polyphen		0.0050	B
Vest4		0.083
MPC		0.15
ClinPred		0.027	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.18
gMVP		0.48
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs232777; hg19: chr1-59125683; COSMIC: COSV68977175;