chr7-141919153-A-T

Position:

• chr7-141919153-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001001656.3(OR9A4):​c.278A>T​(p.Tyr93Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y93C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: OR9A4 NM_001001656.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

Genes affected

OR9A4 (HGNC:15095): (olfactory receptor family 9 subfamily A 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]

MGAM (HGNC:7043): (maltase-glucoamylase) This gene encodes maltase-glucoamylase, which is a brush border membrane enzyme that plays a role in the final steps of digestion of starch. The protein has two catalytic sites identical to those of sucrase-isomaltase, but the proteins are only 59% homologous. Both are members of glycosyl hydrolase family 31, which has a variety of substrate specificities. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0474723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR9A4	NM_001001656.3	c.278A>T	p.Tyr93Phe	missense_variant	2/2	ENST00000641559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR9A4	ENST00000641559.1	c.278A>T	p.Tyr93Phe	missense_variant	2/2		NM_001001656.3	P1
OR9A4	ENST00000548136.1	c.278A>T	p.Tyr93Phe	missense_variant	1/1			P1
MGAM	ENST00000465654.5	c.-180+11285A>T		intron_variant		3
MGAM	ENST00000497554.1	n.37-10624A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251100 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

Feb 28, 2024

The c.278A>T (p.Y93F) alteration is located in exon 1 (coding exon 1) of the OR9A4 gene. This alteration results from a A to T substitution at nucleotide position 278, causing the tyrosine (Y) at amino acid position 93 to be replaced by a phenylalanine (F). 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	0.088
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0050	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.69	.;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.075	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.020	.;N
REVEL	Benign	0.094
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.018	.;D
Polyphen		0.0010	B;B
Vest4		0.18
MutPred		0.47		Loss of catalytic residue at I92 (P = 0.2127);Loss of catalytic residue at I92 (P = 0.2127);
MVP		0.29
MPC		0.034
ClinPred		0.13	T
GERP RS		2.9
Varity_R		0.059
gMVP		0.22

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: rs782101774; hg19: chr7-141618953;