chr1-197084405-C-T

Variant names:

• chr1-197084405-C-T
• rs764134423
• NM_018136.5:c.10353G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_018136.5(ASPM):​c.10353G>A​(p.Leu3451Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,602,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.122
• 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):

• 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-197084405-C-T is Benign according to our data. Variant chr1-197084405-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3604504.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.122 with no splicing effect.

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.10353G>A	p.Leu3451Leu	synonymous	Exon 28 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.5598G>A	p.Leu1866Leu	synonymous	Exon 27 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.10353G>A	p.Leu3451Leu	synonymous	Exon 28 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.5598G>A	p.Leu1866Leu	synonymous	Exon 27 of 27	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.3640G>A		non_coding_transcript_exon	Exon 18 of 18

Frequencies

GnomAD3 genomes AF: 0.0000202 AC: 3 AN: 148880 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000587

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000481 AC: 12 AN: 249254 AF XY: 0.0000371

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000601

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1453970 Hom.: 0 Cov.: 32 AF XY: 0.00000829 AC XY: 6 AN XY: 723698

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.0000224 AC: 1 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105830

Other (OTH) AF: 0.0000166 AC: 1 AN: 60080

GnomAD4 genome AF: 0.0000202 AC: 3 AN: 148880 Hom.: 0 Cov.: 31 AF XY: 0.0000277 AC XY: 2 AN XY: 72314

African (AFR) AF: 0.00 AC: 0 AN: 40512

American (AMR) AF: 0.00 AC: 0 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.000587 AC: 3 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67354

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	4.8
DANN	Benign	0.69
PhyloP100		0.12
Mutation Taster		=98/2	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: rs764134423; hg19: chr1-197053535;