rs151050191

Variant names:

• chr1-197143606-C-T
• rs151050191
• NM_018136.5:c.646G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018136.5(ASPM):​c.646G>A​(p.Glu216Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,084 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (12 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 3.41
• Publications: 10 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):

• microcephaly 5, primary, autosomal recessive

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067848563).
• BP6: Variant 1-197143606-C-T is Benign according to our data. Variant chr1-197143606-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157855.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00104 (1516/1460836) while in subpopulation MID AF = 0.00347 (20/5768). AF 95% confidence interval is 0.0023. There are 12 homozygotes in GnomAdExome4. There are 773 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.646G>A	p.Glu216Lys	missense	Exon 3 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.646G>A	p.Glu216Lys	missense	Exon 3 of 27	NP_001193775.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.646G>A	p.Glu216Lys	missense	Exon 3 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.646G>A	p.Glu216Lys	missense	Exon 3 of 27	ENSP00000294732.7
	ASPM	ENST00000680265.1		c.646G>A	p.Glu216Lys	missense	Exon 3 of 29	ENSP00000505384.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152130 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00175 AC: 437 AN: 249660 AF XY: 0.00168

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000674

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00104 AC: 1516 AN: 1460836 Hom.: 12 Cov.: 36 AF XY: 0.00106 AC XY: 773 AN XY: 726754

African (AFR) AF: 0.000120 AC: 4 AN: 33472

American (AMR) AF: 0.00105 AC: 47 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0330 AC: 863 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52518

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000349 AC: 388 AN: 1111908

Other (OTH) AF: 0.00308 AC: 186 AN: 60384

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152248 Hom.: 2 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74448

African (AFR) AF: 0.0000722 AC: 3 AN: 41570

American (AMR) AF: 0.00177 AC: 27 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67968

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00153 Hom.: 9

Bravo AF: 0.00151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	2	-	Microcephaly 5, primary, autosomal recessive (2)
-	-	2	not specified (2)
-	-	1	ASPM-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.054	T
Polyphen		0.031	B
Vest4		0.30
MVP		0.61
ClinPred		0.033	T
GERP RS		5.2
Varity_R		0.24
gMVP		0.44
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs151050191; hg19: chr1-197112736; COSMIC: COSV54126431; COSMIC: COSV54126431;