rs112647911

Variant names:

• chr1-197101334-T-C
• rs112647911
• NM_018136.5:c.7917A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018136.5(ASPM):​c.7917A>G​(p.Lys2639Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,611,236 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (18 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.765
• Publications: 1 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=-0.78).
• BP6: Variant 1-197101334-T-C is Benign according to our data. Variant chr1-197101334-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.765 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00897 (1362/151902) while in subpopulation AFR AF = 0.0291 (1208/41502). AF 95% confidence interval is 0.0277. There are 18 homozygotes in GnomAd4. There are 635 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.7917A>G	p.Lys2639Lys	synonymous	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5170A>G		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.7917A>G	p.Lys2639Lys	synonymous	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-5170A>G		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-5170A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00876 AC: 1330 AN: 151784 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00257

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000663

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00311 AC: 772 AN: 248498 AF XY: 0.00263

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000714

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00152 AC: 2222 AN: 1459334 Hom.: 18 Cov.: 42 AF XY: 0.00149 AC XY: 1079 AN XY: 726020

African (AFR) AF: 0.0293 AC: 978 AN: 33404

American (AMR) AF: 0.00227 AC: 101 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 413 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52556

Middle Eastern (MID) AF: 0.00690 AC: 39 AN: 5652

European-Non Finnish (NFE) AF: 0.000359 AC: 399 AN: 1111092

Other (OTH) AF: 0.00442 AC: 266 AN: 60244

GnomAD4 genome AF: 0.00897 AC: 1362 AN: 151902 Hom.: 18 Cov.: 32 AF XY: 0.00855 AC XY: 635 AN XY: 74264

African (AFR) AF: 0.0291 AC: 1208 AN: 41502

American (AMR) AF: 0.00257 AC: 39 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000663 AC: 45 AN: 67836

Other (OTH) AF: 0.00570 AC: 12 AN: 2104

Alfa AF: 0.00671 Hom.: 8

Bravo AF: 0.00989

Asia WGS AF: 0.00433 AC: 15 AN: 3476

EpiCase AF: 0.00147

EpiControl AF: 0.00143

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.6
DANN	Benign	0.54
PhyloP100		0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs112647911; hg19: chr1-197070464;