1-197090994-A-G

Variant names:

• chr1-197090994-A-G
• rs143931757
• NM_018136.5:c.9492T>C

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.9492T>C​(p.Tyr3164Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,612,366 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (27 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.423
• Publications: 5 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=-0.85).
• BP6: Variant 1-197090994-A-G is Benign according to our data. Variant chr1-197090994-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000953 (145/152154) while in subpopulation SAS AF = 0.0116 (56/4820). AF 95% confidence interval is 0.00919. There are 2 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.9492T>C	p.Tyr3164Tyr	synonymous	Exon 23 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4737T>C	p.Tyr1579Tyr	synonymous	Exon 22 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.9492T>C	p.Tyr3164Tyr	synonymous	Exon 23 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4737T>C	p.Tyr1579Tyr	synonymous	Exon 22 of 27	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2779T>C		non_coding_transcript_exon	Exon 13 of 18

Frequencies

GnomAD3 genomes AF: 0.000947 AC: 144 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00244 AC: 611 AN: 250210 AF XY: 0.00319

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00994

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000469

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00128 AC: 1871 AN: 1460212 Hom.: 27 Cov.: 31 AF XY: 0.00171 AC XY: 1242 AN XY: 726470

African (AFR) AF: 0.000150 AC: 5 AN: 33422

American (AMR) AF: 0.000269 AC: 12 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 298 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39614

South Asian (SAS) AF: 0.0132 AC: 1136 AN: 86212

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53150

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5762

European-Non Finnish (NFE) AF: 0.000250 AC: 278 AN: 1110934

Other (OTH) AF: 0.00204 AC: 123 AN: 60328

GnomAD4 genome AF: 0.000953 AC: 145 AN: 152154 Hom.: 2 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74384

African (AFR) AF: 0.000265 AC: 11 AN: 41536

American (AMR) AF: 0.000197 AC: 3 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 67990

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.000657

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.43
DANN	Benign	0.39
PhyloP100		0.42
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: rs143931757; hg19: chr1-197060124; COSMIC: COSV107321068;