chr1-197084431-T-TA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_018136.5(ASPM):​c.10332-6dupT 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8679 hom., cov: 0)
  • Exomes 𝑓: 0.31 (2077 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASPM NM_018136.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-197084431-T-TA is Benign according to our data. Variant chr1-197084431-T-TA is described in ClinVar as [Benign]. Clinvar id is 1238332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.10332-6dupT		splice_region_variant, intron_variant	Intron 27 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.5577-6dupT		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.10332-6_10332-5insT		splice_region_variant, intron_variant	Intron 27 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.334 AC: 47758 AN: 143130 Hom.: 8683 Cov.: 0

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.348

GnomAD2 exomes AF: 0.287 AC: 49740 AN: 173358 AF XY: 0.290

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.198

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.310

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.311 AC: 387665 AN: 1246144 Hom.: 2077 Cov.: 0 AF XY: 0.310 AC XY: 193995 AN XY: 626200

African (AFR) AF: 0.163 AC: 4645 AN: 28532

American (AMR) AF: 0.191 AC: 7612 AN: 39914

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 7528 AN: 23830

East Asian (EAS) AF: 0.166 AC: 6036 AN: 36440

South Asian (SAS) AF: 0.251 AC: 19382 AN: 77362

European-Finnish (FIN) AF: 0.284 AC: 12296 AN: 43308

Middle Eastern (MID) AF: 0.302 AC: 1495 AN: 4954

European-Non Finnish (NFE) AF: 0.333 AC: 312791 AN: 939046

Other (OTH) AF: 0.301 AC: 15880 AN: 52758

GnomAD4 genome AF: 0.334 AC: 47764 AN: 143188 Hom.: 8679 Cov.: 0 AF XY: 0.328 AC XY: 22755 AN XY: 69382

African (AFR) AF: 0.175 AC: 6753 AN: 38676

American (AMR) AF: 0.287 AC: 4104 AN: 14296

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1404 AN: 3362

East Asian (EAS) AF: 0.180 AC: 883 AN: 4918

South Asian (SAS) AF: 0.296 AC: 1334 AN: 4500

European-Finnish (FIN) AF: 0.371 AC: 3252 AN: 8756

Middle Eastern (MID) AF: 0.469 AC: 134 AN: 286

European-Non Finnish (NFE) AF: 0.440 AC: 28856 AN: 65546

Other (OTH) AF: 0.346 AC: 678 AN: 1962

Alfa AF: 0.235 Hom.: 495

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.44
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: rs200839523; hg19: chr1-197053561; COSMIC: COSV54126000;