NM_173481.4:c.375C>T

Variant names:

• chr19-757321-C-T
• rs35869813
• NM_173481.4:c.375C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_173481.4(MISP):​c.375C>T​(p.Arg125Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00831 in 1,613,988 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (70 hom.)
• Consequence: MISP NM_173481.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.51
• Publications: 3 publications found

Genes affected

MISP (HGNC:27000): (mitotic spindle positioning) The protein encoded by this gene is an actin-bundling protein involved in determining cell morphology and mitotic progression. The encoded protein is required for the proper positioning of the mitotic spindle. Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-757321-C-T is Benign according to our data. Variant chr19-757321-C-T is described in ClinVar as Benign. ClinVar VariationId is 779178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.51 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173481.4. 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
	MISP	NM_173481.4	MANE Select	c.375C>T	p.Arg125Arg	synonymous	Exon 2 of 5	NP_775752.1	Q8IVT2
	MISP	NR_135168.2		n.61-2588C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MISP	ENST00000215582.8	TSL:1 MANE Select	c.375C>T	p.Arg125Arg	synonymous	Exon 2 of 5	ENSP00000215582.4	Q8IVT2
	MISP	ENST00000871265.1		c.375C>T	p.Arg125Arg	synonymous	Exon 2 of 5	ENSP00000541324.1
	MISP	ENST00000871267.1		c.375C>T	p.Arg125Arg	synonymous	Exon 2 of 5	ENSP00000541326.1

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 953 AN: 152202 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00614 AC: 1532 AN: 249690 AF XY: 0.00600

Gnomad AFR exome AF: 0.00199

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00324

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00607

GnomAD4 exome AF: 0.00852 AC: 12454 AN: 1461668 Hom.: 70 Cov.: 33 AF XY: 0.00827 AC XY: 6016 AN XY: 727134

African (AFR) AF: 0.00146 AC: 49 AN: 33476

American (AMR) AF: 0.00398 AC: 178 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00155 AC: 134 AN: 86254

European-Finnish (FIN) AF: 0.00349 AC: 186 AN: 53340

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11427 AN: 1111930

Other (OTH) AF: 0.00739 AC: 446 AN: 60376

GnomAD4 genome AF: 0.00626 AC: 953 AN: 152320 Hom.: 4 Cov.: 33 AF XY: 0.00615 AC XY: 458 AN XY: 74480

African (AFR) AF: 0.00171 AC: 71 AN: 41578

American (AMR) AF: 0.00666 AC: 102 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0107 AC: 726 AN: 68016

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00758 Hom.: 4

Bravo AF: 0.00664

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.0109

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.54
PhyloP100		1.5
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: rs35869813; hg19: chr19-757321; COSMIC: COSV99297257; COSMIC: COSV99297257;