rs145645602

Variant names:

• chr1-197103120-T-C
• rs145645602
• NM_018136.5:c.6131A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018136.5(ASPM):​c.6131A>G​(p.Asn2044Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,612,732 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2044H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.734
• 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

ENSG00000300054 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045434535).

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.6131A>G	p.Asn2044Ser	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-6956A>G		intron	N/A	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.6131A>G	p.Asn2044Ser	missense	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-6956A>G		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-6956A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151926 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249954 AF XY: 0.000111

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000259 AC: 378 AN: 1460806 Hom.: 0 Cov.: 41 AF XY: 0.000244 AC XY: 177 AN XY: 726710

African (AFR) AF: 0.0000299 AC: 1 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000334 AC: 371 AN: 1111434

Other (OTH) AF: 0.0000994 AC: 6 AN: 60334

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 151926 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74204

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000437

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	Microcephaly 5, primary, autosomal recessive (4)
-	2	1	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.9
DANN	Benign	0.95
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.64	N
PhyloP100		0.73
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.062
Sift	Benign	0.21	T
Sift4G	Benign	0.14	T
Polyphen		0.21	B
Vest4		0.055
MVP		0.11
ClinPred		0.025	T
GERP RS		1.8
Varity_R		0.090
gMVP		0.032
Mutation Taster		=85/15	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: rs145645602; hg19: chr1-197072250;