rs113161395

Positions:

• chr1-197128621-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000367409.9(ASPM):​c.2805T>C​(p.Ser935=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,613,798 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 32)
  • Exomes 𝑓: 0.012 (139 hom.)
• Consequence: ASPM ENST00000367409.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.540

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-197128621-A-G is Benign according to our data. Variant chr1-197128621-A-G is described in ClinVar as [Benign]. Clinvar id is 21567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197128621-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1592/152236) while in subpopulation NFE AF= 0.0144 (979/68008). AF 95% confidence interval is 0.0136. There are 22 homozygotes in gnomad4. There are 824 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.2805T>C	p.Ser935=	synonymous_variant	10/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.2805T>C	p.Ser935=	synonymous_variant	10/27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.2805T>C	p.Ser935=	synonymous_variant	10/28	1	NM_018136.5	ENSP00000356379	P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1594 AN: 152118 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.0104 AC: 2621 AN: 251366 Hom.: 32 AF XY: 0.0103 AC XY: 1402 AN XY: 135870

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.0121 AC: 17688 AN: 1461562 Hom.: 139 Cov.: 31 AF XY: 0.0121 AC XY: 8769 AN XY: 727108

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.0345

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.00997

GnomAD4 genome AF: 0.0105 AC: 1592 AN: 152236 Hom.: 22 Cov.: 32 AF XY: 0.0111 AC XY: 824 AN XY: 74450

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0120 Hom.: 7

Bravo AF: 0.00697

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ASPM: BP4, BP7, BS1, BS2 -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2016	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. -

ASPM-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.3
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs113161395; hg19: chr1-197097751;