rs77191836

Variant names:

• chr1-197133338-C-T
• rs77191836
• NM_018136.5:c.2419+12G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018136.5(ASPM):​c.2419+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,599,632 control chromosomes in the GnomAD database, including 342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (28 hom., cov: 32)
  • Exomes 𝑓: 0.020 (314 hom.)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.718

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 (BayesDel_noAF=-0.84).
• BP6: Variant 1-197133338-C-T is Benign according to our data. Variant chr1-197133338-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197133338-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2725/152228) while in subpopulation NFE AF= 0.0212 (1444/67994). AF 95% confidence interval is 0.0203. There are 28 homozygotes in gnomad4. There are 1277 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.2419+12G>A		intron_variant	Intron 6 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.2419+12G>A		intron_variant	Intron 6 of 26		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.2419+12G>A		intron_variant	Intron 6 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2728 AN: 152110 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0162 AC: 3913 AN: 241242 Hom.: 35 AF XY: 0.0164 AC XY: 2132 AN XY: 130380

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0155

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0195 AC: 28253 AN: 1447404 Hom.: 314 Cov.: 31 AF XY: 0.0192 AC XY: 13833 AN XY: 718606

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0156

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.0214

Gnomad4 OTH exome AF: 0.0195

GnomAD4 genome AF: 0.0179 AC: 2725 AN: 152228 Hom.: 28 Cov.: 32 AF XY: 0.0172 AC XY: 1277 AN XY: 74446

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.0162

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0182 Hom.: 4

Bravo AF: 0.0182

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Microcephaly 5, primary, autosomal recessive Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs77191836; hg19: chr1-197102468;