chr1-197093092-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018136.5(ASPM):c.9254T>C(p.Ile3085Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,611,970 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0016 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 12 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.859

Publications

6 publications found

Variant links:

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):

autosomal recessive primary microcephaly
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
microcephaly 5, primary, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ASPM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011438727).

BP6

Variant 1-197093092-A-G is Benign according to our data. Variant chr1-197093092-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157906.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00161 (245/152010) while in subpopulation AMR AF = 0.00494 (75/15196). AF 95% confidence interval is 0.00404. There are 3 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018136.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.9254T>C	p.Ile3085Thr	missense	Exon 21 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4499T>C	p.Ile1500Thr	missense	Exon 20 of 27	NP_001193775.1	Q8IZT6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASPM	ENST00000367409.9	TSL:1 MANE Select	c.9254T>C	p.Ile3085Thr	missense	Exon 21 of 28	ENSP00000356379.4	Q8IZT6-1
ASPM	ENST00000294732.11	TSL:1	c.4499T>C	p.Ile1500Thr	missense	Exon 20 of 27	ENSP00000294732.7	Q8IZT6-2
ASPM	ENST00000367408.6	TSL:1	n.2541T>C		non_coding_transcript_exon	Exon 11 of 18

Frequencies

GnomAD3 genomes

AF:

0.00161

AC:

245

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00494

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00164

AC:

410

AN:

250014

AF XY:

0.00185

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00185

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.00194

AC:

2829

AN:

1459960

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

1473

AN XY:

726312

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33404

American (AMR)

AF:

0.00150

AC:

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.000126

AC:

AN:

39622

South Asian (SAS)

AF:

0.00443

AC:

382

AN:

86202

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00204

AC:

2270

AN:

1110742

Other (OTH)

AF:

0.00148

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

141

282

424

565

706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00161

AC:

245

AN:

152010

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41538

American (AMR)

AF:

0.00494

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00394

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00191

AC:

130

AN:

67892

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00150

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00175

AC:

212

Asia WGS

AF:

0.00202

AC:

AN:

3476

EpiCase

AF:

0.00169

EpiControl

AF:

0.00225

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Microcephaly 5, primary, autosomal recessive (2)

ASPM-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

9.5

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.019

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.67

M_CAP

Benign

0.0066

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

PhyloP100

0.86

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.96

REVEL

Benign

0.21

Sift

Benign

0.28

Sift4G

Benign

0.17

Polyphen

0.0090

Vest4

0.23

MVP

0.055

ClinPred

0.0017

GERP RS

4.2

Varity_R

0.036

gMVP

0.024

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over