chr1-197129196-G-A

Variant names:

• chr1-197129196-G-A
• rs33987824
• NM_018136.5:c.2751C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018136.5(ASPM):​c.2751C>T​(p.Ala917Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,611,552 control chromosomes in the GnomAD database, including 318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (13 hom., cov: 32)
  • Exomes 𝑓: 0.018 (305 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.721
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-197129196-G-A is Benign according to our data. Variant chr1-197129196-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.721 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0134 (2039/152112) while in subpopulation NFE AF = 0.0201 (1366/67958). AF 95% confidence interval is 0.0192. There are 13 homozygotes in GnomAd4. There are 970 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.2751C>T	p.Ala917Ala	synonymous	Exon 9 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.2751C>T	p.Ala917Ala	synonymous	Exon 9 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.2751C>T	p.Ala917Ala	synonymous	Exon 9 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.2751C>T	p.Ala917Ala	synonymous	Exon 9 of 27	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.182C>T		non_coding_transcript_exon	Exon 2 of 18

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2041 AN: 151994 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00695

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.0149 AC: 3753 AN: 251078 AF XY: 0.0156

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00559

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0180 AC: 26238 AN: 1459440 Hom.: 305 Cov.: 31 AF XY: 0.0176 AC XY: 12808 AN XY: 726100

African (AFR) AF: 0.00239 AC: 80 AN: 33436

American (AMR) AF: 0.00537 AC: 240 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 807 AN: 26082

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39532

South Asian (SAS) AF: 0.0105 AC: 904 AN: 85964

European-Finnish (FIN) AF: 0.0211 AC: 1124 AN: 53386

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5752

European-Non Finnish (NFE) AF: 0.0198 AC: 21985 AN: 1110320

Other (OTH) AF: 0.0170 AC: 1027 AN: 60276

GnomAD4 genome AF: 0.0134 AC: 2039 AN: 152112 Hom.: 13 Cov.: 32 AF XY: 0.0130 AC XY: 970 AN XY: 74358

African (AFR) AF: 0.00345 AC: 143 AN: 41502

American (AMR) AF: 0.00694 AC: 106 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4818

European-Finnish (FIN) AF: 0.0238 AC: 252 AN: 10580

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0201 AC: 1366 AN: 67958

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.0179 Hom.: 45

Bravo AF: 0.0116

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.0171

EpiControl AF: 0.0185

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Microcephaly 5, primary, autosomal recessive (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.2
DANN	Benign	0.66
PhyloP100		-0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs33987824; hg19: chr1-197098326; COSMIC: COSV54129985;