NM_006337.5:c.1217A>G

Variant names:

• chr12-49558928-T-C
• rs772190952
• NM_006337.5:c.1217A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006337.5(MCRS1):​c.1217A>G​(p.Asn406Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,460,612 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: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: MCRS1 NM_006337.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54
• Publications: 2 publications found

Genes affected

MCRS1 (HGNC:6960): (microspherule protein 1) Enables RNA binding activity and telomerase inhibitor activity. Involved in histone H4 acetylation; negative regulation of DNA metabolic process; and positive regulation of protein localization to nucleolus. Located in cytoplasm; nucleolus; and nucleoplasm. Part of Ino80 complex; MLL1 complex; and histone acetyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006337.5. 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
	MCRS1	NM_006337.5	MANE Select	c.1217A>G	p.Asn406Ser	missense	Exon 14 of 15	NP_006328.2
	MCRS1	NM_001012300.1		c.1256A>G	p.Asn419Ser	missense	Exon 13 of 14	NP_001012300.1	Q96EZ8-2
	MCRS1	NM_001278341.2		c.644A>G	p.Asn215Ser	missense	Exon 12 of 13	NP_001265270.1	Q96EZ8-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCRS1	ENST00000343810.9	TSL:1 MANE Select	c.1217A>G	p.Asn406Ser	missense	Exon 14 of 15	ENSP00000345358.4	Q96EZ8-1
	MCRS1	ENST00000357123.8	TSL:1	c.1256A>G	p.Asn419Ser	missense	Exon 13 of 14	ENSP00000349640.4	Q96EZ8-2
	MCRS1	ENST00000546244.5	TSL:1	c.644A>G	p.Asn215Ser	missense	Exon 12 of 13	ENSP00000444982.1	Q96EZ8-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250212 AF XY: 0.0000148

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 FIN exome AF: 0.0000483

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1460612 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 726640

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000336 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.77
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.79		Gain of MoRF binding (P = 0.2613)
MVP		0.93
MPC		1.2
ClinPred		0.76	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.73
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs772190952; hg19: chr12-49952711;