1-197102169-G-C

Position:

• chr1-197102169-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018136.5(ASPM):​c.7082C>G​(p.Ser2361Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.49

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.7082C>G	p.Ser2361Cys	missense_variant	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4066-6005C>G		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.7082C>G	p.Ser2361Cys	missense_variant	18/28	1	NM_018136.5	ENSP00000356379	P1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151744 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 41

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151744 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74084

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.43
Sift	Benign	0.051	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.39
MVP		0.81
ClinPred		0.76	D
GERP RS		3.5
Varity_R		0.088
gMVP		0.028

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

LitVar

Other links and lift over

dbSNP: rs368151024; hg19: chr1-197071299;