11-57712009-C-A

Variant names:

• chr11-57712009-C-A
• rs575304143
• NM_001317078.4:c.171G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001317078.4(MED19):​c.171G>T​(p.Lys57Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000131 in 1,531,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: MED19 NM_001317078.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.763
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1792635).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317078.4. 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
	MED19	NM_001317078.4	MANE Select	c.171G>T	p.Lys57Asn	missense	Exon 1 of 5	NP_001304007.2	J3KR33
	MED19	NM_153450.4		c.171G>T	p.Lys57Asn	missense	Exon 1 of 4	NP_703151.3	A0JLT2-2
	MED19	NR_157587.1		n.207G>T		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED19	ENST00000431606.5	TSL:1 MANE Select	c.171G>T	p.Lys57Asn	missense	Exon 1 of 5	ENSP00000416227.4	J3KR33
	MED19	ENST00000337672.9	TSL:1	c.171G>T	p.Lys57Asn	missense	Exon 1 of 4	ENSP00000337340.4	A0JLT2-2
	MED19	ENST00000534677.1	TSL:1	n.213G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000714 AC: 1 AN: 140052 AF XY: 0.0000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1378912 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 678332

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30474

American (AMR) AF: 0.00 AC: 0 AN: 33102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24398

East Asian (EAS) AF: 0.00 AC: 0 AN: 34530

South Asian (SAS) AF: 0.00 AC: 0 AN: 78094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067910

Other (OTH) AF: 0.0000176 AC: 1 AN: 56836

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.88	T
PhyloP100		0.76
PrimateAI	Pathogenic	0.82	D
REVEL	Benign	0.089
MVP		0.30
MPC		0.95
ClinPred		0.87	D
GERP RS		3.0
PromoterAI		-0.080	Neutral
Mutation Taster		=77/23	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: rs575304143; hg19: chr11-57479481;