Genetic Variant ENST00000641760.1:c.422C>A (chr11-55638779-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000641760.1(OR4P4):c.422C>A(p.Thr141Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000791 in 1,492,428 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 2 hom., cov: 25)

Exomes 𝑓: 0.000080 ( 18 hom. )

Consequence

OR4P4
ENST00000641760.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.31

Publications

1 publications found

Variant links:

Genes affected

OR4P4 (HGNC:15180): (olfactory receptor family 4 subfamily P member 4) Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms. [provided by RefSeq, Jul 2008]

OR4P4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037874818).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000641760.1. 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
	OR4P4	NM_001405919.1	MANE Select	c.422C>A	p.Thr141Lys	missense	Exon 2 of 2	NP_001392848.1	Q8NGL7
	OR4P4	NM_001004124.2		c.422C>A	p.Thr141Lys	missense	Exon 1 of 1	NP_001004124.1	Q8NGL7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR4P4	ENST00000641760.1	MANE Select	c.422C>A	p.Thr141Lys	missense	Exon 2 of 2	ENSP00000493384.1	Q8NGL7

Frequencies

GnomAD3 genomes

AF:

0.0000720

AC:

AN:

138886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000751

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000782

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:

0.0000961

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000574

AC:

AN:

226376

AF XY:

0.0000734

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000960

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000798

AC:

108

AN:

1353456

Hom.:

Cov.:

AF XY:

0.0000683

AC XY:

AN XY:

673142

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32906

American (AMR)

AF:

0.0000269

AC:

AN:

37178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24258

East Asian (EAS)

AF:

0.00

AC:

AN:

34558

South Asian (SAS)

AF:

0.00

AC:

AN:

80452

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5030

European-Non Finnish (NFE)

AF:

0.000100

AC:

104

AN:

1035222

Other (OTH)

AF:

0.0000358

AC:

AN:

55924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000720

AC:

AN:

138972

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

67504

show subpopulations

African (AFR)

AF:

0.0000749

AC:

AN:

40054

American (AMR)

AF:

0.0000781

AC:

AN:

12804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3226

East Asian (EAS)

AF:

0.00

AC:

AN:

4212

South Asian (SAS)

AF:

0.00

AC:

AN:

4280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0000961

AC:

AN:

62418

Other (OTH)

AF:

0.00

AC:

AN:

1852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000125

AC:

ExAC

AF:

0.0000355

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.73

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.0055

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.078

M_CAP

Benign

0.0014

MetaRNN

Benign

0.038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.36

PhyloP100

-2.3

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.6

REVEL

Benign

0.042

Sift

Benign

0.15

Sift4G

Benign

0.077

Polyphen

0.053

Vest4

0.14

MVP

0.25

MPC

0.021

ClinPred

0.049

GERP RS

-3.3

Varity_R

0.085

gMVP

0.12

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over