rs4915337

Variant names:

• chr1-197122407-A-T
• rs4915337
• NM_018136.5:c.3579T>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018136.5(ASPM):​c.3579T>A​(p.Ser1193Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 1,613,582 control chromosomes in the GnomAD database, including 641,187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (49988 hom., cov: 32)
  • Exomes 𝑓: 0.90 (591199 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.295
• Publications: 27 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-197122407-A-T is Benign according to our data. Variant chr1-197122407-A-T is described in ClinVar as Benign. ClinVar VariationId is 21578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.3579T>A	p.Ser1193Ser	synonymous	Exon 14 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.3579T>A	p.Ser1193Ser	synonymous	Exon 14 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.3579T>A	p.Ser1193Ser	synonymous	Exon 14 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.3579T>A	p.Ser1193Ser	synonymous	Exon 14 of 27	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.1621T>A		non_coding_transcript_exon	Exon 5 of 18

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119166 AN: 152002 Hom.: 49965 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.814

GnomAD2 exomes AF: 0.887 AC: 222653 AN: 250926 AF XY: 0.894

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.934

Gnomad ASJ exome AF: 0.893

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.896 AC: 1309791 AN: 1461462 Hom.: 591199 Cov.: 58 AF XY: 0.898 AC XY: 652601 AN XY: 727040

African (AFR) AF: 0.434 AC: 14516 AN: 33460

American (AMR) AF: 0.929 AC: 41524 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 23488 AN: 26120

East Asian (EAS) AF: 1.00 AC: 39672 AN: 39682

South Asian (SAS) AF: 0.899 AC: 77491 AN: 86236

European-Finnish (FIN) AF: 0.932 AC: 49779 AN: 53402

Middle Eastern (MID) AF: 0.868 AC: 5006 AN: 5768

European-Non Finnish (NFE) AF: 0.904 AC: 1004975 AN: 1111734

Other (OTH) AF: 0.883 AC: 53340 AN: 60378

GnomAD4 genome AF: 0.784 AC: 119239 AN: 152120 Hom.: 49988 Cov.: 32 AF XY: 0.789 AC XY: 58651 AN XY: 74374

African (AFR) AF: 0.451 AC: 18712 AN: 41466

American (AMR) AF: 0.872 AC: 13309 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 3126 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5164 AN: 5170

South Asian (SAS) AF: 0.898 AC: 4341 AN: 4832

European-Finnish (FIN) AF: 0.929 AC: 9844 AN: 10600

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.910 AC: 61882 AN: 67996

Other (OTH) AF: 0.816 AC: 1725 AN: 2114

Alfa AF: 0.902 Hom.: 47170

Bravo AF: 0.765

Asia WGS AF: 0.920 AC: 3198 AN: 3478

EpiCase AF: 0.906

EpiControl AF: 0.909

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.5
DANN	Benign	0.53
PhyloP100		-0.29
Mutation Taster		=99/1	polymorphism (auto)

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: rs4915337; hg19: chr1-197091537;