NM_013308.4:c.552T>G

Variant names:

• chr3-151198835-A-C
• NM_013308.4:c.552T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013308.4(GPR171):​c.552T>G​(p.Cys184Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPR171 NM_013308.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.527
• Publications: 0 publications found

Genes affected

GPR171 (HGNC:30057): (G protein-coupled receptor 171) Predicted to enable G protein-coupled purinergic nucleotide receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Predicted to act upstream of or within negative regulation of myeloid cell differentiation. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

MED12L (HGNC:16050): (mediator complex subunit 12L) The protein encoded by this gene is part of the Mediator complex, which is involved in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. The Mediator complex links gene-specific transcriptional activators with the basal transcription machinery. [provided by RefSeq, May 2010]

MED12L Gene-Disease associations (from GenCC):

• Nizon-Isidor syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013308.4. 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
	GPR171	NM_013308.4	MANE Select	c.552T>G	p.Cys184Trp	missense	Exon 3 of 3	NP_037440.3
	MED12L	NM_001393769.1	MANE Select	c.2250+5169A>C		intron	N/A	NP_001380698.1	A0A8I5KX78
	MED12L	NM_053002.6		c.2145+5169A>C		intron	N/A	NP_443728.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR171	ENST00000309180.6	TSL:1 MANE Select	c.552T>G	p.Cys184Trp	missense	Exon 3 of 3	ENSP00000308479.5	O14626
	MED12L	ENST00000687756.1	MANE Select	c.2250+5169A>C		intron	N/A	ENSP00000508695.1	A0A8I5KX78
	MED12L	ENST00000474524.5	TSL:1	c.2145+5169A>C		intron	N/A	ENSP00000417235.1	Q86YW9-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.53
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.015	D
Sift4G	Benign	0.18	T
Polyphen		0.92	P
Vest4		0.67
MutPred		0.68		Gain of MoRF binding (P = 0.057)
MVP		0.44
MPC		0.89
ClinPred		0.97	D
GERP RS		-4.1
Varity_R		0.92
gMVP		0.95
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

hg19: chr3-150916622;