rs112113370

chr1-197143245-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018136.5(ASPM):c.1007C>A(p.Thr336Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000591 in 1,612,252 control chromosomes in the GnomAD database, including 10 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T336T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00092 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (8 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.699

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044797957).
• BP6: Variant 1-197143245-G-T is Benign according to our data. Variant chr1-197143245-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157769.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00092 (140/152224) while in subpopulation EAS AF= 0.0201 (104/5180). AF 95% confidence interval is 0.017. There are 2 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.1007C>A	p.Thr336Lys	missense_variant	3/28	ENST00000367409.9
ASPM	NM_001206846.2	c.1007C>A	p.Thr336Lys	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.1007C>A	p.Thr336Lys	missense_variant	3/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.000868 AC: 132 AN: 152106 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00141 AC: 352 AN: 249660 Hom.: 4 AF XY: 0.00119 AC XY: 161 AN XY: 135342

Gnomad AFR exome AF: 0.000768

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0180

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000557 AC: 813 AN: 1460028 Hom.: 8 Cov.: 33 AF XY: 0.000549 AC XY: 399 AN XY: 726308

Gnomad4 AFR exome AF: 0.00135

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0178

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000763

GnomAD4 genome AF: 0.000920 AC: 140 AN: 152224 Hom.: 2 Cov.: 33 AF XY: 0.00106 AC XY: 79 AN XY: 74450

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0201

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00100 Hom.: 6

Bravo AF: 0.000820

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00123 AC: 149

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 27, 2013	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2015	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

ASPM-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2019

This variant is classified as 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.80
Dann	Benign	0.49
DEOGEN2	Benign	0.019	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.012
Sift	Benign	0.37	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.020	B;.
Vest4		0.068
MVP		0.24
ClinPred		0.00017	T
GERP RS		1.2
Varity_R		0.023
gMVP		0.34

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: rs112113370; hg19: chr1-197112375;