rs113611857

Variant names:

• chr1-197139806-C-A
• rs113611857
• NM_018136.5:c.1987G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018136.5(ASPM):​c.1987G>T​(p.Ala663Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,612,032 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts 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. A663V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (14 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.17
• Publications: 2 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006286055).
• BP6: Variant 1-197139806-C-A is Benign according to our data. Variant chr1-197139806-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157790.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 = 0.0063 (958/152180) while in subpopulation AFR AF = 0.0216 (895/41510). AF 95% confidence interval is 0.0204. There are 8 homozygotes in GnomAd4. There are 448 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.1987G>T	p.Ala663Ser	missense	Exon 4 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.1987G>T	p.Ala663Ser	missense	Exon 4 of 27	NP_001193775.1	Q8IZT6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.1987G>T	p.Ala663Ser	missense	Exon 4 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.1987G>T	p.Ala663Ser	missense	Exon 4 of 27	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000680265.1		c.1987G>T	p.Ala663Ser	missense	Exon 4 of 29	ENSP00000505384.1	A0A7P0Z491

Frequencies

GnomAD3 genomes AF: 0.00629 AC: 956 AN: 152062 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

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: 0.000235

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00160 AC: 402 AN: 251444 AF XY: 0.00119

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000645 AC: 942 AN: 1459852 Hom.: 14 Cov.: 30 AF XY: 0.000604 AC XY: 439 AN XY: 726334

African (AFR) AF: 0.0217 AC: 724 AN: 33426

American (AMR) AF: 0.00150 AC: 67 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5756

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1110288

Other (OTH) AF: 0.00166 AC: 100 AN: 60310

GnomAD4 genome AF: 0.00630 AC: 958 AN: 152180 Hom.: 8 Cov.: 33 AF XY: 0.00602 AC XY: 448 AN XY: 74404

African (AFR) AF: 0.0216 AC: 895 AN: 41510

American (AMR) AF: 0.00262 AC: 40 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68002

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00193 Hom.: 4

Bravo AF: 0.00709

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00197 AC: 239

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Microcephaly 5, primary, autosomal recessive (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.036	D
Sift4G	Uncertain	0.019	D
Polyphen		0.67	P
Vest4		0.28
MVP		0.58
ClinPred		0.015	T
GERP RS		5.8
Varity_R		0.12
gMVP		0.39
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs113611857; hg19: chr1-197108936; COSMIC: COSV54135403; COSMIC: COSV54135403;