chr11-72015122-G-C

Variant names:

• chr11-72015122-G-C
• rs3750913
• NM_006185.4:c.2381C>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006185.4(NUMA1):​c.2381C>G​(p.Ala794Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,613,474 control chromosomes in the GnomAD database, including 817 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.029 (59 hom., cov: 33)
  • Exomes 𝑓: 0.031 (758 hom.)
• Consequence: NUMA1 NM_006185.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.45

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]

ENSG00000251143 (HGNC:58252):

LOC100128494 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024774969).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUMA1	NM_006185.4	c.2381C>G	p.Ala794Gly	missense_variant	Exon 15 of 27	ENST00000393695.8	NP_006176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUMA1	ENST00000393695.8	c.2381C>G	p.Ala794Gly	missense_variant	Exon 15 of 27	1	NM_006185.4	ENSP00000377298.4

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4363 AN: 152220 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.0741

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0345

GnomAD3 exomes AF: 0.0340 AC: 8501 AN: 249898 Hom.: 172 AF XY: 0.0354 AC XY: 4785 AN XY: 135214

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.0465

Gnomad EAS exome AF: 0.0761

Gnomad SAS exome AF: 0.0426

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0313

Gnomad OTH exome AF: 0.0345

GnomAD4 exome AF: 0.0305 AC: 44593 AN: 1461136 Hom.: 758 Cov.: 35 AF XY: 0.0313 AC XY: 22741 AN XY: 726896

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.0225

Gnomad4 ASJ exome AF: 0.0465

Gnomad4 EAS exome AF: 0.0631

Gnomad4 SAS exome AF: 0.0449

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.0284

Gnomad4 OTH exome AF: 0.0335

GnomAD4 genome AF: 0.0287 AC: 4366 AN: 152338 Hom.: 59 Cov.: 33 AF XY: 0.0296 AC XY: 2207 AN XY: 74482

Gnomad4 AFR AF: 0.0181

Gnomad4 AMR AF: 0.0255

Gnomad4 ASJ AF: 0.0455

Gnomad4 EAS AF: 0.0735

Gnomad4 SAS AF: 0.0424

Gnomad4 FIN AF: 0.0244

Gnomad4 NFE AF: 0.0305

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0323 Hom.: 27

Bravo AF: 0.0289

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.0189 AC: 83

ESP6500EA AF: 0.0274 AC: 235

ExAC AF: 0.0341 AC: 4146

Asia WGS AF: 0.0480 AC: 170 AN: 3478

EpiCase AF: 0.0335

EpiControl AF: 0.0332

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	.;T;.;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.64	.;T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;N;.;.;N
REVEL	Benign	0.072
Sift	Uncertain	0.015	D;D;.;.;T
Sift4G	Uncertain	0.052	T;D;T;D;.
Polyphen		0.031	B;B;B;.;.
Vest4		0.12
MPC		0.73
ClinPred		0.031	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.031

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: rs3750913; hg19: chr11-71726168; COSMIC: COSV61184078; COSMIC: COSV61184078;