rs4915337

Variant names:

• chr1-197122407-A-T
• rs4915337
• NM_018136.5:c.3579T>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018136.5(ASPM):​c.3579T>A​(p.Ser1193Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 1,613,582 control chromosomes in the GnomAD database, including 641,187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (49988 hom., cov: 32)
  • Exomes 𝑓: 0.90 (591199 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.295
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-197122407-A-T is Benign according to our data. Variant chr1-197122407-A-T is described in ClinVar as Benign. ClinVar VariationId is 21578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.3579T>A	p.Ser1193Ser	synonymous_variant	Exon 14 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.3579T>A	p.Ser1193Ser	synonymous_variant	Exon 14 of 27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.3579T>A	p.Ser1193Ser	synonymous_variant	Exon 14 of 28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119166 AN: 152002 Hom.: 49965 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.814

GnomAD2 exomes AF: 0.887 AC: 222653 AN: 250926 AF XY: 0.894

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.934

Gnomad ASJ exome AF: 0.893

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.896 AC: 1309791 AN: 1461462 Hom.: 591199 Cov.: 58 AF XY: 0.898 AC XY: 652601 AN XY: 727040

African (AFR) AF: 0.434 AC: 14516 AN: 33460

American (AMR) AF: 0.929 AC: 41524 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 23488 AN: 26120

East Asian (EAS) AF: 1.00 AC: 39672 AN: 39682

South Asian (SAS) AF: 0.899 AC: 77491 AN: 86236

European-Finnish (FIN) AF: 0.932 AC: 49779 AN: 53402

Middle Eastern (MID) AF: 0.868 AC: 5006 AN: 5768

European-Non Finnish (NFE) AF: 0.904 AC: 1004975 AN: 1111734

Other (OTH) AF: 0.883 AC: 53340 AN: 60378

GnomAD4 genome AF: 0.784 AC: 119239 AN: 152120 Hom.: 49988 Cov.: 32 AF XY: 0.789 AC XY: 58651 AN XY: 74374

African (AFR) AF: 0.451 AC: 18712 AN: 41466

American (AMR) AF: 0.872 AC: 13309 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 3126 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5164 AN: 5170

South Asian (SAS) AF: 0.898 AC: 4341 AN: 4832

European-Finnish (FIN) AF: 0.929 AC: 9844 AN: 10600

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.910 AC: 61882 AN: 67996

Other (OTH) AF: 0.816 AC: 1725 AN: 2114

Alfa AF: 0.902 Hom.: 47170

Bravo AF: 0.765

Asia WGS AF: 0.920 AC: 3198 AN: 3478

EpiCase AF: 0.906

EpiControl AF: 0.909

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Benign:4 Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 28, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:4

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 02, 2017

Athena Diagnostics

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

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: 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	-0.85
CADD	Benign	4.5
DANN	Benign	0.53
PhyloP100		-0.29
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4915337; hg19: chr1-197091537;