11-55638757-A-G

Position:

• chr11-55638757-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001004124.2(OR4P4):​c.400A>G​(p.Met134Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,492,658 control chromosomes in the GnomAD database, including 482 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (22 hom., cov: 26)
  • Exomes 𝑓: 0.0017 (460 hom.)
• Consequence: OR4P4 NM_001004124.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.90

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019891202).
• BP6: Variant 11-55638757-A-G is Benign according to our data. Variant chr11-55638757-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2343498.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR4P4	NM_001004124.2	c.400A>G	p.Met134Val	missense_variant	1/1		NP_001004124.1
OR4P4	NM_001405919.1	c.400A>G	p.Met134Val	missense_variant	2/2		NP_001392848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR4P4	ENST00000641760.1	c.400A>G	p.Met134Val	missense_variant	2/2			ENSP00000493384.1

Frequencies

GnomAD3 genomes AF: 0.000893 AC: 124 AN: 138878 Hom.: 22 Cov.: 26

Gnomad AFR AF: 0.000427

Gnomad AMI AF: 0.00122

Gnomad AMR AF: 0.000781

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000545

GnomAD3 exomes AF: 0.000773 AC: 175 AN: 226246 Hom.: 31 AF XY: 0.000873 AC XY: 107 AN XY: 122594

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000564

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000708

Gnomad FIN exome AF: 0.0000523

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000543

GnomAD4 exome AF: 0.00169 AC: 2288 AN: 1353692 Hom.: 460 Cov.: 31 AF XY: 0.00161 AC XY: 1083 AN XY: 673284

Gnomad4 AFR exome AF: 0.000274

Gnomad4 AMR exome AF: 0.000753

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000208

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.000892 AC: 124 AN: 138966 Hom.: 22 Cov.: 26 AF XY: 0.000874 AC XY: 59 AN XY: 67520

Gnomad4 AFR AF: 0.000425

Gnomad4 AMR AF: 0.000780

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000111

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.000545

Alfa AF: 0.000818 Hom.: 1

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000459 AC: 2

ESP6500EA AF: 0.00199 AC: 16

ExAC AF: 0.000771 AC: 87

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.400A>G (p.M134V) alteration is located in exon 1 (coding exon 1) of the OR4P4 gene. This alteration results from a A to G substitution at nucleotide position 400, causing the methionine (M) at amino acid position 134 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

OR4P4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.0091	T;T
Eigen	Benign	-0.027
Eigen_PC	Benign	0.043
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	.;D
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.2	.;D
REVEL	Benign	0.18
Sift	Benign	0.041	.;D
Sift4G	Uncertain	0.028	.;D
Polyphen		0.0050	B;B
Vest4		0.56
MVP		0.29
MPC		0.11
ClinPred		0.040	T
GERP RS		4.8
Varity_R		0.34
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147136011; hg19: chr11-55406233;