NM_001059.3:c.1246A>T

Variant names:

• chr4-103589834-T-A
• rs143073792
• NM_001059.3:c.1246A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001059.3(TACR3):​c.1246A>T​(p.Asn416Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,613,920 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N416N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: TACR3 NM_001059.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.69
• Publications: 3 publications found

Genes affected

TACR3 (HGNC:11528): (tachykinin receptor 3) This gene belongs to a family of genes that function as receptors for tachykinins. Receptor affinities are specified by variations in the 5'-end of the sequence. The receptors belonging to this family are characterized by interactions with G proteins and 7 hydrophobic transmembrane regions. This gene encodes the receptor for the tachykinin neurokinin 3, also referred to as neurokinin B. [provided by RefSeq, Jul 2008]

TACR3-AS1 (HGNC:55593): (TACR3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043549538).
• BP6: Variant 4-103589834-T-A is Benign according to our data. Variant chr4-103589834-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 347107.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00145 (220/152220) while in subpopulation NFE AF = 0.00107 (73/68006). AF 95% confidence interval is 0.000875. There are 2 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001059.3. 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
	TACR3	NM_001059.3	MANE Select	c.1246A>T	p.Asn416Tyr	missense	Exon 5 of 5	NP_001050.1	P29371
	TACR3-AS1	NR_186501.1		n.190-1373T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TACR3	ENST00000304883.3	TSL:1 MANE Select	c.1246A>T	p.Asn416Tyr	missense	Exon 5 of 5	ENSP00000303325.2	P29371
	TACR3-AS1	ENST00000502936.1	TSL:2	n.190-1373T>A		intron	N/A
	TACR3-AS1	ENST00000512401.5	TSL:2	n.292-1373T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152102 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00145 AC: 365 AN: 251186 AF XY: 0.00147

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00115 AC: 1681 AN: 1461700 Hom.: 2 Cov.: 32 AF XY: 0.00111 AC XY: 805 AN XY: 727150

African (AFR) AF: 0.000120 AC: 4 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00906 AC: 484 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00104 AC: 1159 AN: 1111862

Other (OTH) AF: 0.000563 AC: 34 AN: 60384

GnomAD4 genome AF: 0.00145 AC: 220 AN: 152220 Hom.: 2 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74434

African (AFR) AF: 0.000168 AC: 7 AN: 41548

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68006

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000506

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00133 AC: 161

EpiCase AF: 0.00120

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Hypogonadotropic hypogonadism 11 with or without anosmia (1)
-	-	1	not specified (1)
-	-	1	TACR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.035	D
Polyphen		0.24	B
Vest4		0.10
MVP		0.85
MPC		0.41
ClinPred		0.039	T
GERP RS		4.4
Varity_R		0.068
gMVP		0.39
Mutation Taster		=94/6	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: rs143073792; hg19: chr4-104510991;