11-57705079-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001317078.4(MED19):​c.368A>G​(p.Asp123Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,614,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MED19
NM_001317078.4 missense

Scores

10
2
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75
Variant links:
Genes affected
MED19 (HGNC:29600): (mediator complex subunit 19) The protein encoded by this gene is a subunit of the Mediator complex, which binds to gene-specific regulatory factors and provides support for the basal RNA polymerase II transcription machinery. This gene has been implicated in the growth of several types of cancer, and inhibition of its expression inhibits the growth and spread of these cancers. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED19NM_001317078.4 linkc.368A>G p.Asp123Gly missense_variant Exon 2 of 5 ENST00000431606.5 NP_001304007.2 A0JLT2
MED19NM_153450.4 linkc.368A>G p.Asp123Gly missense_variant Exon 2 of 4 NP_703151.3 A0JLT2-2
MED19NR_157587.1 linkn.404A>G non_coding_transcript_exon_variant Exon 2 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED19ENST00000431606.5 linkc.368A>G p.Asp123Gly missense_variant Exon 2 of 5 1 NM_001317078.4 ENSP00000416227.4 J3KR33

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152148
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00329
Gnomad AMR
AF:
0.000131
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:
0.000206
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000103
AC:
26
AN:
251494
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000193
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000121
AC:
177
AN:
1461892
Hom.:
0
Cov.:
33
AF XY:
0.000110
AC XY:
80
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000144
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152266
Hom.:
0
Cov.:
31
AF XY:
0.0000806
AC XY:
6
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000213
Hom.:
0
Bravo
AF:
0.000147
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000382
EpiControl
AF:
0.000415

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 15, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.368A>G (p.D123G) alteration is located in exon 2 (coding exon 2) of the MED19 gene. This alteration results from a A to G substitution at nucleotide position 368, causing the aspartic acid (D) at amino acid position 123 to be replaced by a glycine (G). 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
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Uncertain
0.029
D
PrimateAI
Pathogenic
0.79
T
REVEL
Pathogenic
0.94
MVP
0.57
MPC
1.5
ClinPred
0.69
D
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.49
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.49
Position offset: 1

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: rs180753680; hg19: chr11-57472551; API