rs114737609

chr1-197142801-T-C

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.1451A>G(p.Asn484Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,613,730 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N484D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (12 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.587

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 (MetaRNN=0.0029534101).
• BP6: Variant 1-197142801-T-C is Benign according to our data. Variant chr1-197142801-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 157781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0073 (1111/152286) while in subpopulation AFR AF= 0.0254 (1055/41564). AF 95% confidence interval is 0.0241. There are 13 homozygotes in gnomad4. There are 487 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.1451A>G	p.Asn484Ser	missense_variant	3/28	ENST00000367409.9
ASPM	NM_001206846.2	c.1451A>G	p.Asn484Ser	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.1451A>G	p.Asn484Ser	missense_variant	3/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.00728 AC: 1108 AN: 152168 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00211 AC: 531 AN: 251076 Hom.: 5 AF XY: 0.00149 AC XY: 202 AN XY: 135758

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000818 AC: 1196 AN: 1461444 Hom.: 12 Cov.: 33 AF XY: 0.000704 AC XY: 512 AN XY: 727044

Gnomad4 AFR exome AF: 0.0262

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00730 AC: 1111 AN: 152286 Hom.: 13 Cov.: 33 AF XY: 0.00654 AC XY: 487 AN XY: 74492

Gnomad4 AFR AF: 0.0254

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00142 Hom.: 4

Bravo AF: 0.00858

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00250 AC: 303

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Microcephaly 5, primary, autosomal recessive Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.1
Dann	Benign	0.68
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.088	N
LIST_S2	Uncertain	0.87	D;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.021
Sift	Benign	0.65	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	B;.
Vest4		0.074
MVP		0.28
ClinPred		0.0015	T
GERP RS		2.3
Varity_R		0.033
gMVP		0.063

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: rs114737609; hg19: chr1-197111931;