rs113161395

Variant names:

• chr1-197128621-A-G
• rs113161395
• NM_018136.5:c.2805T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_018136.5(ASPM):​c.2805T>C​(p.Ser935Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,613,798 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 32)
  • Exomes 𝑓: 0.012 (139 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.540
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-197128621-A-G is Benign according to our data. Variant chr1-197128621-A-G is described in ClinVar as Benign. ClinVar VariationId is 21567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1592/152236) while in subpopulation NFE AF = 0.0144 (979/68008). AF 95% confidence interval is 0.0136. There are 22 homozygotes in GnomAd4. There are 824 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.2805T>C	p.Ser935Ser	synonymous	Exon 10 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.2805T>C	p.Ser935Ser	synonymous	Exon 10 of 27	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.2805T>C	p.Ser935Ser	synonymous	Exon 10 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.2805T>C	p.Ser935Ser	synonymous	Exon 10 of 27	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.757T>C		non_coding_transcript_exon	Exon 2 of 18

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1594 AN: 152118 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.0104 AC: 2621 AN: 251366 AF XY: 0.0103

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.0121 AC: 17688 AN: 1461562 Hom.: 139 Cov.: 31 AF XY: 0.0121 AC XY: 8769 AN XY: 727108

African (AFR) AF: 0.00179 AC: 60 AN: 33476

American (AMR) AF: 0.00199 AC: 89 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 110 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00157 AC: 135 AN: 86246

European-Finnish (FIN) AF: 0.0345 AC: 1845 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0133 AC: 14841 AN: 1111738

Other (OTH) AF: 0.00997 AC: 602 AN: 60386

GnomAD4 genome AF: 0.0105 AC: 1592 AN: 152236 Hom.: 22 Cov.: 32 AF XY: 0.0111 AC XY: 824 AN XY: 74450

African (AFR) AF: 0.00202 AC: 84 AN: 41560

American (AMR) AF: 0.00353 AC: 54 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.0412 AC: 436 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0144 AC: 979 AN: 68008

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.0120 Hom.: 7

Bravo AF: 0.00697

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0108

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.3
DANN	Benign	0.76
PhyloP100		0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs113161395; hg19: chr1-197097751;