chr6-118815033-G-A

Position:

• chr6-118815033-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017696.3(MCM9):​c.3223C>T​(p.Pro1075Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,550,360 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (21 hom.)
• Consequence: MCM9 NM_017696.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.723

Genes affected

MCM9 (HGNC:21484): (minichromosome maintenance 9 homologous recombination repair factor) The protein encoded by this gene is a member of the mini-chromosome maintenance (MCM) protein family that are essential for the initiation of eukaryotic genome replication. Binding of this protein to chromatin has been shown to be a pre-requisite for recruiting the MCM2-7 helicase to DNA replication origins. This protein also binds, and is a positive regulator of, the chromatin licensing and DNA replication factor 1, CDT1. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004585713).
• BP6: Variant 6-118815033-G-A is Benign according to our data. Variant chr6-118815033-G-A is described in ClinVar as [Benign]. Clinvar id is 782477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1566/152214) while in subpopulation AFR AF= 0.0357 (1480/41508). AF 95% confidence interval is 0.0341. There are 29 homozygotes in gnomad4. There are 741 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM9	NM_017696.3	c.3223C>T	p.Pro1075Ser	missense_variant	14/14	ENST00000619706.5	NP_060166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM9	ENST00000619706.5	c.3223C>T	p.Pro1075Ser	missense_variant	14/14	5	NM_017696.3	ENSP00000480469	P1
MCM9	ENST00000316316.10	c.3223C>T	p.Pro1075Ser	missense_variant	13/13	5		ENSP00000314505	P1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1564 AN: 152096 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00220 AC: 329 AN: 149834 Hom.: 3 AF XY: 0.00166 AC XY: 133 AN XY: 80256

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000307

Gnomad OTH exome AF: 0.00206

GnomAD4 exome AF: 0.00109 AC: 1517 AN: 1398146 Hom.: 21 Cov.: 31 AF XY: 0.000953 AC XY: 657 AN XY: 689522

Gnomad4 AFR exome AF: 0.0359

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00346

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000769

Gnomad4 OTH exome AF: 0.00241

GnomAD4 genome AF: 0.0103 AC: 1566 AN: 152214 Hom.: 29 Cov.: 32 AF XY: 0.00996 AC XY: 741 AN XY: 74400

Gnomad4 AFR AF: 0.0357

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00166 Hom.: 3

Bravo AF: 0.0119

ExAC AF: 0.00245 AC: 52

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MCM9: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.57	.;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.060
Sift	Benign	0.18	T;.
Sift4G	Benign	0.40	T;T
Polyphen		0.22	B;B
Vest4		0.17
MVP		0.43
MPC		0.16
ClinPred		0.012	T
GERP RS		3.3
Varity_R		0.048
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs61744508; hg19: chr6-119136196;