X-131544078-C-A

Variant names:

• chrX-131544078-C-A
• rs1360450855
• NM_001004486.1:c.5C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004486.1(OR13H1):​c.5C>A​(p.Ala2Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000943 in 1,059,922 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 1 hem.)
• Consequence: OR13H1 NM_001004486.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 0 publications found

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]

IGSF1 Gene-Disease associations (from GenCC):

• X-linked central congenital hypothyroidism with late-onset testicular enlargement

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049499393).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004486.1. 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
	OR13H1	NM_001004486.1	MANE Select	c.5C>A	p.Ala2Asp	missense	Exon 1 of 1	NP_001004486.1	Q8NG92

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR13H1	ENST00000338616.6	TSL:6 MANE Select	c.5C>A	p.Ala2Asp	missense	Exon 1 of 1	ENSP00000340748.3	Q8NG92
	IGSF1	ENST00000370904.6	TSL:2	c.-913+34590G>T		intron	N/A	ENSP00000359941.1	Q8N6C5-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.43e-7 AC: 1 AN: 1059922 Hom.: 0 Cov.: 27 AF XY: 0.00000296 AC XY: 1 AN XY: 337960

African (AFR) AF: 0.00 AC: 0 AN: 25606

American (AMR) AF: 0.00 AC: 0 AN: 33151

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17301

East Asian (EAS) AF: 0.00 AC: 0 AN: 29833

South Asian (SAS) AF: 0.0000205 AC: 1 AN: 48708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39389

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3956

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 817463

Other (OTH) AF: 0.00 AC: 0 AN: 44515

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.078
DANN	Benign	0.23
DEOGEN2	Benign	0.0010	T
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.11	N
PhyloP100		-1.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.0080
Sift	Benign	0.50	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.075
MutPred		0.18		Loss of catalytic residue at A2 (P = 0.074)
MVP		0.43
MPC		0.023
ClinPred		0.023	T
GERP RS		1.7
PromoterAI		-0.059	Neutral
Varity_R		0.092
gMVP		0.18
Mutation Taster		=99/1	polymorphism

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: rs1360450855; hg19: chrX-130678052;