1-197124231-G-A

Position:

• chr1-197124231-G-A

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.3269C>T​(p.Ser1090Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 1,609,054 control chromosomes in the GnomAD database, including 833 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (442 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (391 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 1.91

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017031133).
• BP6: Variant 1-197124231-G-A is Benign according to our data. Variant chr1-197124231-G-A is described in ClinVar as [Benign]. Clinvar id is 21575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197124231-G-A is described in Lovd as [Benign]. Variant chr1-197124231-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.3269C>T	p.Ser1090Phe	missense_variant	13/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.3269C>T	p.Ser1090Phe	missense_variant	13/27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.3269C>T	p.Ser1090Phe	missense_variant	13/28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6289 AN: 151936 Hom.: 442 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0109 AC: 2722 AN: 250632 Hom.: 165 AF XY: 0.00756 AC XY: 1024 AN XY: 135518

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.00788

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00434 AC: 6320 AN: 1457000 Hom.: 391 Cov.: 31 AF XY: 0.00365 AC XY: 2649 AN XY: 725198

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.00864

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000233

Gnomad4 OTH exome AF: 0.00953

GnomAD4 genome AF: 0.0414 AC: 6296 AN: 152054 Hom.: 442 Cov.: 32 AF XY: 0.0400 AC XY: 2977 AN XY: 74338

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.00694 Hom.: 97

Bravo AF: 0.0468

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.144 AC: 634

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.0134 AC: 1630

Asia WGS AF: 0.00754 AC: 26 AN: 3462

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 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	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 09, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -

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

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.079
Sift	Uncertain	0.028	D;T;T
Sift4G	Uncertain	0.011	D;T;D
Polyphen		0.057	B;.;.
Vest4		0.32
ClinPred		0.019	T
GERP RS		3.6
Varity_R		0.041
gMVP		0.38

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: rs16841081; hg19: chr1-197093361;