19-40775859-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006533.4(MIA):​c.235C>T​(p.Arg79Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MIA
NM_006533.4 missense

Scores

3
14
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.42
Variant links:
Genes affected
MIA (HGNC:7076): (MIA SH3 domain containing) Predicted to enable growth factor activity. Predicted to be involved in extracellular matrix organization. Predicted to act upstream of or within cell-matrix adhesion. Predicted to be located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]
MIA-RAB4B (HGNC:48352): (MIA-RAB4B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MIA (melanoma inhibitory activity) and RAB4B (RAB4B, member RAS oncogene family) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MIANM_006533.4 linkc.235C>T p.Arg79Cys missense_variant Exon 2 of 4 ENST00000263369.4 NP_006524.1 Q16674-1A0A024R0P1
MIANM_001202553.2 linkc.235C>T p.Arg79Cys missense_variant Exon 3 of 5 NP_001189482.1 Q16674-1A0A024R0P1
MIA-RAB4BNR_037775.1 linkn.241C>T non_coding_transcript_exon_variant Exon 2 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MIAENST00000263369.4 linkc.235C>T p.Arg79Cys missense_variant Exon 2 of 4 1 NM_006533.4 ENSP00000263369.2 Q16674-1
MIA-RAB4BENST00000600729.2 linkn.235C>T non_coding_transcript_exon_variant Exon 3 of 11 5 ENSP00000472384.1 W4VSR3

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151890
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461866
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000198
AC:
3
AN:
151890
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74164
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 18, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.235C>T (p.R79C) alteration is located in exon 2 (coding exon 2) of the MIA gene. This alteration results from a C to T substitution at nucleotide position 235, causing the arginine (R) at amino acid position 79 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.37
T;T;T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.95
.;.;D
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.66
D;D;D
MetaSVM
Uncertain
0.33
D
MutationAssessor
Uncertain
2.6
M;M;M
PrimateAI
Pathogenic
0.79
T
PROVEAN
Uncertain
-3.4
.;.;D
REVEL
Uncertain
0.60
Sift
Uncertain
0.014
.;.;D
Sift4G
Uncertain
0.050
T;T;T
Polyphen
1.0
D;D;D
Vest4
0.57
MutPred
0.39
Loss of MoRF binding (P = 0.0156);Loss of MoRF binding (P = 0.0156);Loss of MoRF binding (P = 0.0156);
MVP
0.89
MPC
0.97
ClinPred
0.99
D
GERP RS
4.0
Varity_R
0.62
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.25
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.25
Position offset: -26

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748572393; hg19: chr19-41281764; API