1-197090252-T-C

Variant names:

• chr1-197090252-T-C
• rs7528827
• NM_018136.5:c.9773A>G

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.9773A>G​(p.His3258Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,552 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (4 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 2.41
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008112043).
• BP6: Variant 1-197090252-T-C is Benign according to our data. Variant chr1-197090252-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21638.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 = 0.00695 (1057/152190) while in subpopulation AFR AF = 0.0231 (959/41560). AF 95% confidence interval is 0.0219. There are 10 homozygotes in GnomAd4. There are 499 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.9773A>G	p.His3258Arg	missense	Exon 24 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.5018A>G	p.His1673Arg	missense	Exon 23 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.9773A>G	p.His3258Arg	missense	Exon 24 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.5018A>G	p.His1673Arg	missense	Exon 23 of 27	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.3060A>G		non_coding_transcript_exon	Exon 14 of 18

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1056 AN: 152072 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00200 AC: 502 AN: 251068 AF XY: 0.00153

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000810 AC: 1184 AN: 1461362 Hom.: 4 Cov.: 32 AF XY: 0.000719 AC XY: 523 AN XY: 726994

African (AFR) AF: 0.0214 AC: 717 AN: 33452

American (AMR) AF: 0.00212 AC: 95 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86246

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53396

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5756

European-Non Finnish (NFE) AF: 0.000214 AC: 238 AN: 1111720

Other (OTH) AF: 0.00199 AC: 120 AN: 60356

GnomAD4 genome AF: 0.00695 AC: 1057 AN: 152190 Hom.: 10 Cov.: 32 AF XY: 0.00671 AC XY: 499 AN XY: 74388

African (AFR) AF: 0.0231 AC: 959 AN: 41560

American (AMR) AF: 0.00479 AC: 73 AN: 15242

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67972

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00267 Hom.: 13

Bravo AF: 0.00742

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00239 AC: 290

Asia WGS AF: 0.00116 AC: 4 AN: 3472

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Microcephaly 5, primary, autosomal recessive (4)
-	-	3	not provided (3)
-	-	1	ASPM-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.76
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.4
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.060
Sift	Benign	0.20	T
Sift4G	Benign	0.12	T
Polyphen		0.0020	B
Vest4		0.18
MVP		0.24
ClinPred		0.010	T
GERP RS		3.0
Varity_R		0.051
gMVP		0.23
Mutation Taster		=95/5	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: rs7528827; hg19: chr1-197059382; COSMIC: COSV99659556;