rs141108591

Variant names:

• chr1-197146446-C-A
• rs141108591
• NM_018136.5:c.-9G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-197146446-C-A
• chr1-197146446-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018136.5(ASPM):​c.-9G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00061 in 1,605,288 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00059 (11 hom.)
• Consequence: ASPM NM_018136.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.258
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-197146446-C-A is Benign according to our data. Variant chr1-197146446-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000769 (117/152132) while in subpopulation EAS AF = 0.0212 (109/5130). AF 95% confidence interval is 0.018. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.-9G>T		5_prime_UTR	Exon 1 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.-9G>T		5_prime_UTR	Exon 1 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.-9G>T		5_prime_UTR	Exon 1 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.-9G>T		5_prime_UTR	Exon 1 of 27	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000680265.1		c.-9G>T		5_prime_UTR	Exon 1 of 29	ENSP00000505384.1	A0A7P0Z491

Frequencies

GnomAD3 genomes AF: 0.000770 AC: 117 AN: 152010 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00195 AC: 450 AN: 231340 AF XY: 0.00185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0246

Gnomad FIN exome AF: 0.0000608

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.000594 AC: 863 AN: 1453156 Hom.: 11 Cov.: 31 AF XY: 0.000603 AC XY: 436 AN XY: 722930

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.0000448 AC: 2 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.0202 AC: 801 AN: 39668

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47400

Middle Eastern (MID) AF: 0.000231 AC: 1 AN: 4332

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111430

Other (OTH) AF: 0.000565 AC: 34 AN: 60124

GnomAD4 genome AF: 0.000769 AC: 117 AN: 152132 Hom.: 0 Cov.: 31 AF XY: 0.000928 AC XY: 69 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41504

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0212 AC: 109 AN: 5130

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000858 Hom.: 0

Bravo AF: 0.00110

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Microcephaly 5, primary, autosomal recessive (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.6
DANN	Benign	0.39
PhyloP100		-0.26
PromoterAI		-0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=298/2	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: rs141108591; hg19: chr1-197115576;