chr1-197084463-GTTC-G

Variant names:

• chr1-197084463-GTTC-G
• rs537718986
• NM_018136.5:c.10332-40_10332-38delGAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018136.5(ASPM):​c.10332-40_10332-38delGAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,432,470 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0310
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 1-197084463-GTTC-G is Benign according to our data. Variant chr1-197084463-GTTC-G is described in ClinVar as [Likely_benign]. Clinvar id is 1220309.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00521 (785/150634) while in subpopulation AFR AF = 0.0179 (737/41166). AF 95% confidence interval is 0.0168. There are 9 homozygotes in GnomAd4. There are 355 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.10332-40_10332-38delGAA		intron_variant	Intron 27 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.5577-40_5577-38delGAA		intron_variant	Intron 26 of 26		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.10332-40_10332-38delGAA		intron_variant	Intron 27 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 786 AN: 150550 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00266

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00128 AC: 291 AN: 227884 AF XY: 0.00102

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.000391

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000298

Gnomad OTH exome AF: 0.000353

GnomAD4 exome AF: 0.000535 AC: 686 AN: 1281836 Hom.: 7 AF XY: 0.000481 AC XY: 311 AN XY: 646094

African (AFR) AF: 0.0193 AC: 574 AN: 29694

American (AMR) AF: 0.000666 AC: 29 AN: 43534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24916

East Asian (EAS) AF: 0.00 AC: 0 AN: 38422

South Asian (SAS) AF: 0.0000609 AC: 5 AN: 82138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46530

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5332

European-Non Finnish (NFE) AF: 0.0000188 AC: 18 AN: 956906

Other (OTH) AF: 0.00109 AC: 59 AN: 54364

GnomAD4 genome AF: 0.00521 AC: 785 AN: 150634 Hom.: 9 Cov.: 32 AF XY: 0.00484 AC XY: 355 AN XY: 73404

African (AFR) AF: 0.0179 AC: 737 AN: 41166

American (AMR) AF: 0.00265 AC: 40 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10036

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67720

Other (OTH) AF: 0.00287 AC: 6 AN: 2092

Alfa AF: 0.00326 Hom.: 4

Bravo AF: 0.00640

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 28, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.031
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: rs537718986; hg19: chr1-197053593;