X-131544891-T-A

Position:

• chrX-131544891-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001004486.1(OR13H1):​c.818T>A​(p.Ile273Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,207,827 control chromosomes in the GnomAD database, including 3 homozygotes. There are 540 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (2 hom. 516 hem.)
• Consequence: OR13H1 NM_001004486.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.933

Genes affected

OR13H1 (HGNC:14755): (olfactory receptor family 13 subfamily H member 1) 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]

IGSF1 (HGNC:5948): (immunoglobulin superfamily member 1) This gene encodes a member of the immunoglobulin-like domain-containing superfamily. Proteins in this superfamily contain varying numbers of immunoglobulin-like domains and are thought to participate in the regulation of interactions between cells. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053870022).
• BS2: High Hemizygotes in GnomAd4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR13H1	NM_001004486.1	c.818T>A	p.Ile273Asn	missense_variant	1/1	ENST00000338616.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR13H1	ENST00000338616.6	c.818T>A	p.Ile273Asn	missense_variant	1/1		NM_001004486.1	P1
IGSF1	ENST00000370904.6	c.-913+33777A>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 128 AN: 111989 Hom.: 1 Cov.: 23 AF XY: 0.000703 AC XY: 24 AN XY: 34137

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00437

Gnomad AMR AF: 0.000570

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000753

Gnomad FIN AF: 0.00130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000404 AC: 74 AN: 182965 Hom.: 0 AF XY: 0.000296 AC XY: 20 AN XY: 67555

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.000375

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00144 AC: 1582 AN: 1095788 Hom.: 2 Cov.: 29 AF XY: 0.00143 AC XY: 516 AN XY: 361210

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000284

Gnomad4 ASJ exome AF: 0.000361

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000555

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00169

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00114 AC: 128 AN: 112039 Hom.: 1 Cov.: 23 AF XY: 0.000702 AC XY: 24 AN XY: 34197

Gnomad4 AFR AF: 0.000194

Gnomad4 AMR AF: 0.000569

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000755

Gnomad4 FIN AF: 0.00130

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.000735 Hom.: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000997 AC: 121

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.818T>A (p.I273N) alteration is located in exon 1 (coding exon 1) of the OR13H1 gene. This alteration results from a T to A substitution at nucleotide position 818, causing the isoleucine (I) at amino acid position 273 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.25
MVP		0.90
MPC		0.19
ClinPred		0.19	T
GERP RS		4.9
Varity_R		0.89
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs149043680; hg19: chrX-130678865;