NM_018136.5:c.7551T>C

Variant names:

• chr1-197101700-A-G
• rs149228705
• NM_018136.5:c.7551T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018136.5(ASPM):​c.7551T>C​(p.Tyr2517Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,612,040 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -0.180
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-197101700-A-G is Benign according to our data. Variant chr1-197101700-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157870.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000484 (707/1460222) while in subpopulation MID AF = 0.0115 (66/5758). AF 95% confidence interval is 0.00924. There are 4 homozygotes in GnomAdExome4. There are 381 alleles in the male GnomAdExome4 subpopulation. Median coverage is 64. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.7551T>C	p.Tyr2517Tyr	synonymous	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5536T>C		intron	N/A	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.7551T>C	p.Tyr2517Tyr	synonymous	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-5536T>C		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-5536T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151700 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000527

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000457

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000652 AC: 163 AN: 249894 AF XY: 0.000651

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.000639

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000745

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000484 AC: 707 AN: 1460222 Hom.: 4 Cov.: 64 AF XY: 0.000524 AC XY: 381 AN XY: 726408

African (AFR) AF: 0.000299 AC: 10 AN: 33414

American (AMR) AF: 0.000561 AC: 25 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 76 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86206

European-Finnish (FIN) AF: 0.000264 AC: 14 AN: 53082

Middle Eastern (MID) AF: 0.0115 AC: 66 AN: 5758

European-Non Finnish (NFE) AF: 0.000409 AC: 455 AN: 1111164

Other (OTH) AF: 0.000779 AC: 47 AN: 60308

GnomAD4 genome AF: 0.000343 AC: 52 AN: 151818 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74208

African (AFR) AF: 0.0000482 AC: 2 AN: 41470

American (AMR) AF: 0.000527 AC: 8 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000457 AC: 31 AN: 67826

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.000400

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	2	-	Microcephaly 5, primary, autosomal recessive (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.99
DANN	Benign	0.31
PhyloP100		-0.18
Mutation Taster		=100/0	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: rs149228705; hg19: chr1-197070830; COSMIC: COSV54123838;