chr1-197084431-TA-T

Variant names:

• chr1-197084431-TA-T
• rs200839523
• NM_018136.5:c.10332-6delT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_018136.5(ASPM):​c.10332-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 0)
  • Exomes 𝑓: 0.13 (1 hom.)
• Consequence: ASPM NM_018136.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.439
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 1-197084431-TA-T is Benign according to our data. Variant chr1-197084431-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1204775.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.10332-6delT		splice_region_variant, intron_variant	Intron 27 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.5577-6delT		splice_region_variant, 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.10332-6delT		splice_region_variant, intron_variant	Intron 27 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 500 AN: 143052 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00343

Gnomad ASJ AF: 0.00149

Gnomad EAS AF: 0.00142

Gnomad SAS AF: 0.000885

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00180

Gnomad OTH AF: 0.00155

GnomAD2 exomes AF: 0.207 AC: 35898 AN: 173358 AF XY: 0.205

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.290

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.292

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.133 AC: 157885 AN: 1186624 Hom.: 1 Cov.: 0 AF XY: 0.135 AC XY: 80485 AN XY: 594382

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.241 AC: 6274 AN: 26024

American (AMR) AF: 0.252 AC: 9172 AN: 36452

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3186 AN: 22492

East Asian (EAS) AF: 0.261 AC: 8148 AN: 31278

South Asian (SAS) AF: 0.189 AC: 13429 AN: 70998

European-Finnish (FIN) AF: 0.149 AC: 6036 AN: 40570

Middle Eastern (MID) AF: 0.126 AC: 595 AN: 4704

European-Non Finnish (NFE) AF: 0.115 AC: 103924 AN: 904412

Other (OTH) AF: 0.143 AC: 7121 AN: 49694

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00352 AC: 504 AN: 143108 Hom.: 2 Cov.: 0 AF XY: 0.00394 AC XY: 273 AN XY: 69298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00483 AC: 187 AN: 38678

American (AMR) AF: 0.00350 AC: 50 AN: 14286

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 5 AN: 3360

East Asian (EAS) AF: 0.00142 AC: 7 AN: 4916

South Asian (SAS) AF: 0.000889 AC: 4 AN: 4500

European-Finnish (FIN) AF: 0.0149 AC: 130 AN: 8724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00180 AC: 118 AN: 65518

Other (OTH) AF: 0.00153 AC: 3 AN: 1956

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0832 Hom.: 495

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 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		-0.44
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200839523; hg19: chr1-197053561; COSMIC: COSV54124104;