chrX-131544889-T-A

Position:

• chrX-131544889-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.816T>A​(p.Phe272Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,207,241 control chromosomes in the GnomAD database, including 3 homozygotes. There are 539 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. 515 hem.)
• Consequence: OR13H1 NM_001004486.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.220

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=0.007773459).
• BS2: High Hemizygotes in GnomAd4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR13H1	NM_001004486.1	c.816T>A	p.Phe272Leu	missense_variant	1/1	ENST00000338616.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR13H1	ENST00000338616.6	c.816T>A	p.Phe272Leu	missense_variant	1/1		NM_001004486.1	P1
IGSF1	ENST00000370904.6	c.-913+33779A>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 128 AN: 111916 Hom.: 1 Cov.: 23 AF XY: 0.000704 AC XY: 24 AN XY: 34072

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000570

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000752

Gnomad FIN AF: 0.00131

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00134

GnomAD3 exomes AF: 0.000394 AC: 72 AN: 182920 Hom.: 0 AF XY: 0.000281 AC XY: 19 AN XY: 67536

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: 0.000663

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00144 AC: 1578 AN: 1095273 Hom.: 2 Cov.: 29 AF XY: 0.00143 AC XY: 515 AN XY: 360697

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: 0.00168

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00114 AC: 128 AN: 111968 Hom.: 1 Cov.: 23 AF XY: 0.000703 AC XY: 24 AN XY: 34134

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.000569

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000754

Gnomad4 FIN AF: 0.00131

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.000735 Hom.: 2

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.816T>A (p.F272L) 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 816, causing the phenylalanine (F) at amino acid position 272 to be replaced by a leucine (L). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.49
DEOGEN2	Benign	0.0017	T
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.72	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.0070	B
Vest4		0.012
MutPred		0.32		Gain of catalytic residue at F272 (P = 0.0852);
MVP		0.67
MPC		0.023
ClinPred		0.024	T
GERP RS		1.1
Varity_R		0.11
gMVP		0.062

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

Publications

LitVar

Other links and lift over

dbSNP: rs757467764; hg19: chrX-130678863;