rs12138336

Positions:

• chr1-197101391-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018136.5(ASPM):​c.7860G>C​(p.Gln2620His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,608,614 control chromosomes in the GnomAD database, including 4,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2620K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.049 (237 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3957 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.907

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013516843).
• BP6: Variant 1-197101391-C-G is Benign according to our data. Variant chr1-197101391-C-G is described in ClinVar as [Benign]. Clinvar id is 21609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101391-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.7860G>C	p.Gln2620His	missense_variant	18/28	ENST00000367409.9
ASPM	NM_001206846.2	c.4066-5227G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.7860G>C	p.Gln2620His	missense_variant	18/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.0487 AC: 7385 AN: 151702 Hom.: 237 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0840

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0732

Gnomad OTH AF: 0.0572

GnomAD3 exomes AF: 0.0507 AC: 12506 AN: 246592 Hom.: 400 AF XY: 0.0515 AC XY: 6876 AN XY: 133528

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0317

Gnomad ASJ exome AF: 0.0833

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0310

Gnomad FIN exome AF: 0.0533

Gnomad NFE exome AF: 0.0715

Gnomad OTH exome AF: 0.0633

GnomAD4 exome AF: 0.0682 AC: 99283 AN: 1456794 Hom.: 3957 Cov.: 52 AF XY: 0.0674 AC XY: 48851 AN XY: 724822

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0340

Gnomad4 ASJ exome AF: 0.0805

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0322

Gnomad4 FIN exome AF: 0.0564

Gnomad4 NFE exome AF: 0.0770

Gnomad4 OTH exome AF: 0.0643

GnomAD4 genome AF: 0.0486 AC: 7383 AN: 151820 Hom.: 237 Cov.: 32 AF XY: 0.0463 AC XY: 3432 AN XY: 74202

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.0447

Gnomad4 ASJ AF: 0.0840

Gnomad4 EAS AF: 0.000778

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.0529

Gnomad4 NFE AF: 0.0732

Gnomad4 OTH AF: 0.0566

Alfa AF: 0.0668 Hom.: 101

Bravo AF: 0.0474

TwinsUK AF: 0.0731 AC: 271

ALSPAC AF: 0.0732 AC: 282

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.0697 AC: 599

ExAC AF: 0.0502 AC: 6084

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). -

Microcephaly 5, primary, autosomal recessive Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.5
DANN	Benign	0.62
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.084
Sift	Benign	0.14	T
Sift4G	Benign	0.58	T
Polyphen		0.064	B
Vest4		0.063
MutPred		0.19		Loss of ubiquitination at K2618 (P = 0.0801);
ClinPred		0.0079	T
GERP RS		-8.3
Varity_R		0.048
gMVP		0.010

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: rs12138336; hg19: chr1-197070521; COSMIC: COSV54130527;