11-72004687-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006185.4(NUMA1):c.5959C>T(p.Arg1987Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,613,616 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: NUMA1 NM_006185.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29

Genes affected

NUMA1 (HGNC:8059): (nuclear mitotic apparatus protein 1) This gene encodes a large protein that forms a structural component of the nuclear matrix. The encoded protein interacts with microtubules and plays a role in the formation and organization of the mitotic spindle during cell division. Chromosomal translocation of this gene with the RARA (retinoic acid receptor, alpha) gene on chromosome 17 have been detected in patients with acute promyelocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]

IL18BP (HGNC:5987): (interleukin 18 binding protein) The protein encoded by this gene functions as an inhibitor of the proinflammatory cytokine, IL18. It binds IL18, prevents the binding of IL18 to its receptor, and thus inhibits IL18-induced IFN-gamma production, resulting in reduced T-helper type 1 immune responses. This protein is constitutively expressed and secreted in mononuclear cells. Elevated level of this protein is detected in the intestinal tissues of patients with Crohn's disease. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014875233).
• BP6: Variant 11-72004687-G-A is Benign according to our data. Variant chr11-72004687-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 784216.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUMA1	NM_006185.4	c.5959C>T	p.Arg1987Cys	missense_variant	24/27	ENST00000393695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUMA1	ENST00000393695.8	c.5959C>T	p.Arg1987Cys	missense_variant	24/27	1	NM_006185.4	P2

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00133 AC: 333 AN: 251012 Hom.: 1 AF XY: 0.00125 AC XY: 169 AN XY: 135704

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000648

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00169 AC: 2476 AN: 1461322 Hom.: 5 Cov.: 32 AF XY: 0.00157 AC XY: 1143 AN XY: 726966

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74470

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00172 Hom.: 2

Bravo AF: 0.00103

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.00161 AC: 196

EpiCase AF: 0.00120

EpiControl AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.015	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D;D;D;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;D;D;.;.;.
Sift4G	Benign	0.071	T;D;D;D;T;D
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.61
MVP		0.45
MPC		1.2
ClinPred		0.042	T
GERP RS		4.8
Varity_R		0.42
gMVP		0.36

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: rs35681270; hg19: chr11-71715733; COSMIC: COSV52622225; COSMIC: COSV52622225;