rs143805893

chr1-197122420-G-Achr1-197122420-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018136.5(ASPM):c.3566C>T(p.Ser1189Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 1.75

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032462925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.3566C>T	p.Ser1189Phe	missense_variant	14/28	ENST00000367409.9
ASPM	NM_001206846.2	c.3566C>T	p.Ser1189Phe	missense_variant	14/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.3566C>T	p.Ser1189Phe	missense_variant	14/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000307 AC: 77 AN: 250940 Hom.: 0 AF XY: 0.000383 AC XY: 52 AN XY: 135614

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000538

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000551 AC: 806 AN: 1461540 Hom.: 0 Cov.: 35 AF XY: 0.000552 AC XY: 401 AN XY: 727086

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000672

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74456

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000499 Hom.: 1

Bravo AF: 0.000419

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000709

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 12, 2022	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1189 of the ASPM protein (p.Ser1189Phe). This variant is present in population databases (rs143805893, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. ClinVar contains an entry for this variant (Variation ID: 294639). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 17, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	- -

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	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 22, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The c.3566C>T (p.S1189F) alteration is located in exon 14 (coding exon 14) of the ASPM gene. This alteration results from a C to T substitution at nucleotide position 3566, causing the serine (S) at amino acid position 1189 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	15
Dann	Benign	0.93
DEOGEN2	Uncertain	0.42	T;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.86
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	0.50	D;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.091	T;T;T
Polyphen		0.62	P;.;.
Vest4		0.096
MVP		0.25
ClinPred		0.017	T
GERP RS		-5.7
Varity_R		0.034
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143805893; hg19: chr1-197091550;