NM_018136.5:c.7939C>A

Variant names:

• chr1-197101312-G-T
• rs3762271
• NM_018136.5:c.7939C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018136.5(ASPM):​c.7939C>A​(p.Leu2647Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,610,322 control chromosomes in the GnomAD database, including 129,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2647L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (8818 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120761 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.00200
• Publications: 36 publications found

Genes affected

ASPM (HGNC:19048): (assembly factor for spindle microtubules) This gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. Studies in mouse also suggest a role of this gene in mitotic spindle regulation, with a preferential role in regulating neurogenesis. Mutations in this gene are associated with microcephaly primary type 5. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2011]

ASPM Gene-Disease associations (from GenCC):

• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046061575).
• BP6: Variant 1-197101312-G-T is Benign according to our data. Variant chr1-197101312-G-T is described in ClinVar as Benign. ClinVar VariationId is 21611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018136.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.7939C>A	p.Leu2647Ile	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5148C>A		intron	N/A	NP_001193775.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.7939C>A	p.Leu2647Ile	missense	Exon 18 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.4066-5148C>A		intron	N/A	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.2108-5148C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46211 AN: 151428 Hom.: 8822 Cov.: 32

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.329

GnomAD2 exomes AF: 0.334 AC: 83078 AN: 248402 AF XY: 0.345

Gnomad AFR exome AF: 0.0888

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.164

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.397 AC: 579850 AN: 1458776 Hom.: 120761 Cov.: 47 AF XY: 0.397 AC XY: 287812 AN XY: 725780

African (AFR) AF: 0.0826 AC: 2759 AN: 33398

American (AMR) AF: 0.217 AC: 9644 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 10238 AN: 26056

East Asian (EAS) AF: 0.154 AC: 6084 AN: 39592

South Asian (SAS) AF: 0.308 AC: 26531 AN: 86192

European-Finnish (FIN) AF: 0.370 AC: 19598 AN: 52958

Middle Eastern (MID) AF: 0.370 AC: 2092 AN: 5652

European-Non Finnish (NFE) AF: 0.433 AC: 480519 AN: 1110216

Other (OTH) AF: 0.372 AC: 22385 AN: 60214

GnomAD4 genome AF: 0.305 AC: 46211 AN: 151546 Hom.: 8818 Cov.: 32 AF XY: 0.301 AC XY: 22266 AN XY: 74044

African (AFR) AF: 0.0944 AC: 3912 AN: 41438

American (AMR) AF: 0.268 AC: 4060 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1382 AN: 3464

East Asian (EAS) AF: 0.158 AC: 807 AN: 5120

South Asian (SAS) AF: 0.292 AC: 1407 AN: 4816

European-Finnish (FIN) AF: 0.373 AC: 3933 AN: 10544

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29522 AN: 67690

Other (OTH) AF: 0.328 AC: 688 AN: 2098

Alfa AF: 0.386 Hom.: 41099

Bravo AF: 0.286

TwinsUK AF: 0.434 AC: 1609

ALSPAC AF: 0.430 AC: 1656

ESP6500AA AF: 0.104 AC: 460

ESP6500EA AF: 0.435 AC: 3737

ExAC AF: 0.339 AC: 41138

Asia WGS AF: 0.202 AC: 706 AN: 3476

EpiCase AF: 0.422

EpiControl AF: 0.425

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Microcephaly 5, primary, autosomal recessive Benign:3 Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.8
DANN	Benign	0.92
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.0020
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.20
Sift	Benign	0.20	T
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.18
ClinPred		0.0097	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.084
gMVP		0.0030
Mutation Taster		=94/6	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: rs3762271; hg19: chr1-197070442; COSMIC: COSV54126748;