rs151050191

chr1-197143606-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018136.5(ASPM):c.646G>A(p.Glu216Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,084 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (12 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 3.41

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067848563).
• BP6: Variant 1-197143606-C-T is Benign according to our data. Variant chr1-197143606-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157855.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=3, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00104 (1516/1460836) while in subpopulation MID AF= 0.00347 (20/5768). AF 95% confidence interval is 0.0023. There are 12 homozygotes in gnomad4_exome. There are 773 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.646G>A	p.Glu216Lys	missense_variant	3/28	ENST00000367409.9
ASPM	NM_001206846.2	c.646G>A	p.Glu216Lys	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.646G>A	p.Glu216Lys	missense_variant	3/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152130 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00175 AC: 437 AN: 249660 Hom.: 8 AF XY: 0.00168 AC XY: 227 AN XY: 135044

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000674

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00104 AC: 1516 AN: 1460836 Hom.: 12 Cov.: 36 AF XY: 0.00106 AC XY: 773 AN XY: 726754

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.0330

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000349

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152248 Hom.: 2 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74448

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000530

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00232 Hom.: 6

Bravo AF: 0.00151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

Microcephaly 5, primary, autosomal recessive Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2016	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2014

There is insufficient or conflicting evidence for classification of this alteration. -

ASPM-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	20
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.031	B;.
Vest4		0.30
MVP		0.61
ClinPred		0.033	T
GERP RS		5.2
Varity_R		0.24
gMVP		0.44

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: rs151050191; hg19: chr1-197112736; COSMIC: COSV54126431; COSMIC: COSV54126431;