1-168104855-A-T

Variant names:

• chr1-168104855-A-T
• rs200635937
• ENST00000271357.9:c.47T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000682931.1(GPR161):​c.-5T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,612,380 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (49 hom.)
• Consequence: GPR161 ENST00000682931.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 3.04
• Publications: 7 publications found

Genes affected

GPR161 (HGNC:23694): (G protein-coupled receptor 161) The protein encoded by this gene is an orphan G protein-coupled receptor whose ligand is unknown. This gene is overexpressed in triple-negative breast cancer, and disruption of this gene slows the proliferation of basal breast cancer cells. Therefore, this gene is a potential drug target for triple-negative breast cancer. [provided by RefSeq, Mar 2017]

GPR161 Gene-Disease associations (from GenCC):

• pituitary stalk interruption syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000306311 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008036792).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00105 (160/152110) while in subpopulation SAS AF = 0.0245 (118/4814). AF 95% confidence interval is 0.0209. There are 1 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 160 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000682931.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR161	NM_001375883.1	MANE Select	c.-5T>A		5_prime_UTR	Exon 2 of 6	NP_001362812.1
	GPR161	NM_001267609.1		c.56T>A	p.Leu19Gln	missense	Exon 3 of 7	NP_001254538.1
	GPR161	NM_001267611.1		c.47T>A	p.Leu16Gln	missense	Exon 2 of 6	NP_001254540.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR161	ENST00000271357.9	TSL:1	c.47T>A	p.Leu16Gln	missense	Exon 2 of 6	ENSP00000271357.6
	GPR161	ENST00000493800.1	TSL:1	n.55T>A		non_coding_transcript_exon	Exon 1 of 3
	GPR161	ENST00000682931.1	MANE Select	c.-5T>A		5_prime_UTR	Exon 2 of 6	ENSP00000506967.1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 151992 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0245

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00290 AC: 728 AN: 251040 AF XY: 0.00414

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00167 AC: 2436 AN: 1460270 Hom.: 49 Cov.: 32 AF XY: 0.00241 AC XY: 1747 AN XY: 726094

African (AFR) AF: 0.0000598 AC: 2 AN: 33456

American (AMR) AF: 0.000112 AC: 5 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.0227 AC: 1959 AN: 86226

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53398

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5760

European-Non Finnish (NFE) AF: 0.000307 AC: 341 AN: 1110664

Other (OTH) AF: 0.00161 AC: 97 AN: 60310

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152110 Hom.: 1 Cov.: 31 AF XY: 0.00147 AC XY: 109 AN XY: 74358

African (AFR) AF: 0.000169 AC: 7 AN: 41536

American (AMR) AF: 0.000132 AC: 2 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000305 Hom.: 0

Bravo AF: 0.000302

ExAC AF: 0.00332 AC: 403

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Medulloblastoma (1)
1	-	-	Pituitary stalk interruption syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.85	T
PhyloP100		3.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.48
Sift	Benign	0.080	T
Sift4G	Pathogenic	0.0	D
Vest4		0.67
MVP		0.87
MPC		1.1
ClinPred		0.062	T
GERP RS		3.0
gMVP		0.30
Mutation Taster		=294/6	disease causing (ClinVar)

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: rs200635937; hg19: chr1-168074093;