rs141715950

Variant names:

• chr1-197103304-T-A
• rs141715950
• NM_018136.5:c.5947A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-197103304-T-A
• chr1-197103304-T-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.5947A>T​(p.Met1983Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,188 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1983T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 1.66
• Publications: 4 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

ENSG00000300054 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028411925).
• BP6: Variant 1-197103304-T-A is Benign according to our data. Variant chr1-197103304-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157844.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00115 (175/152022) while in subpopulation NFE AF = 0.00193 (131/67882). AF 95% confidence interval is 0.00166. There are 1 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.5947A>T	p.Met1983Leu	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-7140A>T		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.5947A>T	p.Met1983Leu	missense	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-7140A>T		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-7140A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 151904 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000987

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00126 AC: 316 AN: 250464 AF XY: 0.00132

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00189 AC: 2765 AN: 1461166 Hom.: 5 Cov.: 38 AF XY: 0.00187 AC XY: 1361 AN XY: 726906

African (AFR) AF: 0.000179 AC: 6 AN: 33434

American (AMR) AF: 0.000739 AC: 33 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00111 AC: 59 AN: 53362

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00231 AC: 2571 AN: 1111566

Other (OTH) AF: 0.00154 AC: 93 AN: 60358

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152022 Hom.: 1 Cov.: 32 AF XY: 0.000848 AC XY: 63 AN XY: 74328

African (AFR) AF: 0.000361 AC: 15 AN: 41518

American (AMR) AF: 0.000985 AC: 15 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 67882

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00218 Hom.: 3

Bravo AF: 0.00123

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00133 AC: 161

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	2	1	Microcephaly 5, primary, autosomal recessive (3)
-	1	1	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.23
Sift	Benign	0.040	D
Sift4G	Uncertain	0.039	D
Polyphen		0.94	P
Vest4		0.35
MutPred		0.61		Loss of loop (P = 0.1242)
MVP		0.31
ClinPred		0.13	T
GERP RS		5.6
Varity_R		0.46
gMVP		0.043
Mutation Taster		=92/8	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: rs141715950; hg19: chr1-197072434; COSMIC: COSV99661475;