21-46266025-A-T

Variant names:

• chr21-46266025-A-T
• NM_003906.5:c.2931T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003906.5(MCM3AP):​c.2931T>A​(p.His977Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H977H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MCM3AP NM_003906.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.256

Genes affected

MCM3AP (HGNC:6946): (minichromosome maintenance complex component 3 associated protein) The minichromosome maintenance protein 3 (MCM3) is one of the MCM proteins essential for the initiation of DNA replication. The protein encoded by this gene is a MCM3 binding protein. It was reported to have phosphorylation-dependent DNA-primase activity, which was up-regulated in antigen immunization induced germinal center. This protein was demonstrated to be an acetyltransferase that acetylates MCM3 and plays a role in DNA replication. The mutagenesis of a nuclear localization signal of MCM3 affects the binding of this protein with MCM3, suggesting that this protein may also facilitate MCM3 nuclear localization. This gene is expressed in the brain or in neuronal tissue. An allelic variant encoding amino acid Lys at 915, instead of conserved Glu, has been identified in patients with mild intellectual disability. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM3AP	NM_003906.5	c.2931T>A	p.His977Gln	missense_variant	Exon 11 of 28	ENST00000291688.6	NP_003897.2
MCM3AP	XM_005261203.5	c.2931T>A	p.His977Gln	missense_variant	Exon 12 of 29		XP_005261260.1
MCM3AP	XM_005261204.6	c.2931T>A	p.His977Gln	missense_variant	Exon 12 of 29		XP_005261261.1
MCM3AP	XM_005261205.5	c.2931T>A	p.His977Gln	missense_variant	Exon 12 of 29		XP_005261262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM3AP	ENST00000291688.6	c.2931T>A	p.His977Gln	missense_variant	Exon 11 of 28	1	NM_003906.5	ENSP00000291688.1
MCM3AP	ENST00000397708.1	c.2931T>A	p.His977Gln	missense_variant	Exon 12 of 29	5		ENSP00000380820.1
MCM3AP	ENST00000486937.5	n.1223T>A		non_coding_transcript_exon_variant	Exon 2 of 18	2
MCM3AP	ENST00000496607.5	n.928T>A		non_coding_transcript_exon_variant	Exon 1 of 18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459244 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 725696

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Uncertain	0.67	D;D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.85	D;.
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.96	D;D
Vest4		0.40
MutPred		0.28		Gain of solvent accessibility (P = 0.0081);Gain of solvent accessibility (P = 0.0081);
MVP		0.39
MPC		0.57
ClinPred		0.92	D
GERP RS		-0.97
Varity_R		0.62
gMVP		0.63

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: chr21-47685939;