NM_006185.4:c.2381C>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 29 publications found

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]

NUMA1-AS1 (HGNC:58252):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006185.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUMA1	NM_006185.4	MANE Select	c.2381C>G	p.Ala794Gly	missense	Exon 15 of 27	NP_006176.2	Q14980-1
	NUMA1	NM_001286561.2		c.2381C>G	p.Ala794Gly	missense	Exon 16 of 27	NP_001273490.1	Q14980-2
	NUMA1-AS1	NR_104178.2		n.832G>C		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUMA1	ENST00000393695.8	TSL:1 MANE Select	c.2381C>G	p.Ala794Gly	missense	Exon 15 of 27	ENSP00000377298.4	Q14980-1
	NUMA1	ENST00000351960.10	TSL:1	c.1242+1286C>G		intron	N/A	ENSP00000260051.8	Q14980-5
	NUMA1	ENST00000967521.1		c.2381C>G	p.Ala794Gly	missense	Exon 15 of 28	ENSP00000637580.1

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

GnomAD2 exomes AF: 0.0340 AC: 8501 AN: 249898 AF XY: 0.0354

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 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

African (AFR) AF: 0.0177 AC: 593 AN: 33480

American (AMR) AF: 0.0225 AC: 1005 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0465 AC: 1216 AN: 26136

East Asian (EAS) AF: 0.0631 AC: 2505 AN: 39700

South Asian (SAS) AF: 0.0449 AC: 3873 AN: 86258

European-Finnish (FIN) AF: 0.0289 AC: 1521 AN: 52676

Middle Eastern (MID) AF: 0.0485 AC: 280 AN: 5768

European-Non Finnish (NFE) AF: 0.0284 AC: 31577 AN: 1112006

Other (OTH) AF: 0.0335 AC: 2023 AN: 60388

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

African (AFR) AF: 0.0181 AC: 752 AN: 41578

American (AMR) AF: 0.0255 AC: 391 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3472

East Asian (EAS) AF: 0.0735 AC: 381 AN: 5184

South Asian (SAS) AF: 0.0424 AC: 205 AN: 4832

European-Finnish (FIN) AF: 0.0244 AC: 259 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0305 AC: 2078 AN: 68030

Other (OTH) AF: 0.0336 AC: 71 AN: 2110

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 v4.9

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
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.072
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.052	T
Polyphen		0.031	B
Vest4		0.12
MPC		0.73
ClinPred		0.031	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.031
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

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