chr11-72006221-A-G

Position:

• chr11-72006221-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000393695.8(NUMA1):​c.5506T>C​(p.Tyr1836His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0072 in 1,614,202 control chromosomes in the GnomAD database, including 64 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (59 hom.)
• Consequence: NUMA1 ENST00000393695.8 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.70

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050857663).
• BP6: Variant 11-72006221-A-G is Benign according to our data. Variant chr11-72006221-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 774210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72006221-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 862 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUMA1	NM_006185.4	c.5506T>C	p.Tyr1836His	missense_variant	22/27	ENST00000393695.8	NP_006176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUMA1	ENST00000393695.8	c.5506T>C	p.Tyr1836His	missense_variant	22/27	1	NM_006185.4	ENSP00000377298	P2

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 863 AN: 152210 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00989

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00539 AC: 1354 AN: 251266 Hom.: 10 AF XY: 0.00555 AC XY: 754 AN XY: 135830

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00875

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.00688

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00736 AC: 10756 AN: 1461874 Hom.: 59 Cov.: 31 AF XY: 0.00751 AC XY: 5463 AN XY: 727244

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00994

Gnomad4 FIN exome AF: 0.00440

Gnomad4 NFE exome AF: 0.00785

Gnomad4 OTH exome AF: 0.00821

GnomAD4 genome AF: 0.00566 AC: 862 AN: 152328 Hom.: 5 Cov.: 33 AF XY: 0.00514 AC XY: 383 AN XY: 74482

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00989

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00728 Hom.: 13

Bravo AF: 0.00470

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00792 AC: 68

ExAC AF: 0.00543 AC: 659

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00575

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	NUMA1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;T;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.75	.;.;T;T;T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0051	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L;.;.;.
MutationTaster	Benign	0.79	D;D;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N;N;.;.;.
REVEL	Benign	0.032
Sift	Benign	0.031	D;D;D;.;.;.
Sift4G	Benign	0.15	T;D;D;D;T;T
Polyphen		0.0020, 0.0030	.;B;B;B;.;.
Vest4		0.18
MVP		0.33
MPC		0.37
ClinPred		0.0055	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35586429; hg19: chr11-71717267; COSMIC: COSV99474516; COSMIC: COSV99474516;