chr1-197103952-C-G

Variant names:

• chr1-197103952-C-G
• rs142536561
• NM_018136.5:c.5299G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_018136.5(ASPM):​c.5299G>C​(p.Ala1767Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,612,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.79
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00939703).
• BP6: Variant 1-197103952-C-G is Benign according to our data. Variant chr1-197103952-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157833.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0013 (197/152004) while in subpopulation AFR AF = 0.00446 (185/41518). AF 95% confidence interval is 0.00393. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.5299G>C	p.Ala1767Pro	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-7788G>C		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.5299G>C	p.Ala1767Pro	missense	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-7788G>C		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-7788G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 151886 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000376 AC: 94 AN: 250206 AF XY: 0.000229

Gnomad AFR exome AF: 0.00493

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 212 AN: 1460512 Hom.: 0 Cov.: 38 AF XY: 0.000131 AC XY: 95 AN XY: 726592

African (AFR) AF: 0.00449 AC: 150 AN: 33392

American (AMR) AF: 0.000112 AC: 5 AN: 44590

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111410

Other (OTH) AF: 0.000332 AC: 20 AN: 60318

GnomAD4 genome AF: 0.00130 AC: 197 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74306

African (AFR) AF: 0.00446 AC: 185 AN: 41518

American (AMR) AF: 0.000329 AC: 5 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67894

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.00153

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.25
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-1.8
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.32
Sift	Benign	0.21	T
Sift4G	Benign	0.28	T
Polyphen		0.85	P
Vest4		0.17
MVP		0.86
ClinPred		0.056	T
GERP RS		-3.4
Varity_R		0.10
gMVP		0.20
Mutation Taster		=86/14	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: rs142536561; hg19: chr1-197073082;