Genetic Variant MYRIP:p.Gly184Ala (chr3-40166846-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_015460.4(MYRIP):c.551G>C(p.Gly184Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,550 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G184E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MYRIP
NM_015460.4 missense, splice_region

Scores

Splicing: ADA: 0.9996

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.15

Publications

0 publications found

Variant links:

Genes affected

MYRIP (HGNC:19156): (myosin VIIA and Rab interacting protein) Predicted to enable actin binding activity and myosin binding activity. Predicted to be involved in positive regulation of insulin secretion. Predicted to be located in actin cytoskeleton; dense core granule; and perinuclear region of cytoplasm. Predicted to be part of exocyst. Predicted to be active in cortical actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

MYRIP links:

ENTPD3-AS1 (HGNC:):

ENTPD3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015460.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYRIP	NM_015460.4	MANE Select	c.551G>C	p.Gly184Ala	missense splice_region	Exon 6 of 17	NP_056275.2	Q8NFW9-1
MYRIP	NM_001284423.2		c.551G>C	p.Gly184Ala	missense splice_region	Exon 6 of 17	NP_001271352.1	Q8NFW9-1
MYRIP	NM_001284424.2		c.551G>C	p.Gly184Ala	missense splice_region	Exon 6 of 16	NP_001271353.1	Q8NFW9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYRIP	ENST00000302541.11	TSL:1 MANE Select	c.551G>C	p.Gly184Ala	missense splice_region	Exon 6 of 17	ENSP00000301972.6	Q8NFW9-1
MYRIP	ENST00000444716.5	TSL:1	c.551G>C	p.Gly184Ala	missense splice_region	Exon 6 of 17	ENSP00000398665.1	Q8NFW9-1
MYRIP	ENST00000396217.7	TSL:1	c.284G>C	p.Gly95Ala	missense splice_region	Exon 5 of 16	ENSP00000379519.3	Q8NFW9-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449550

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

722020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33224

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100864

Other (OTH)

AF:

0.00

AC:

AN:

59970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.7

PhyloP100

8.1

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.2

REVEL

Benign

0.098

Sift

Uncertain

0.0020

Sift4G

Benign

0.44

Polyphen

1.0

Vest4

0.77

MutPred

0.23

Gain of glycosylation at S182 (P = 0.0155)

MVP

0.75

MPC

0.54

ClinPred

0.90

GERP RS

4.5

Varity_R

0.31

gMVP

0.32

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over