4-103719778-A-G

Variant names:

• chr4-103719778-A-G
• rs3733632
• NM_001059.3:c.-103T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001059.3(TACR3):​c.-103T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,453,798 control chromosomes in the GnomAD database, including 44,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (13302 hom., cov: 32)
  • Exomes 𝑓: 0.19 (31563 hom.)
• Consequence: TACR3 NM_001059.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.13
• Publications: 23 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 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 11 with or without anosmia

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-103719778-A-G is Benign according to our data. Variant chr4-103719778-A-G is described in ClinVar as Benign. ClinVar VariationId is 347119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

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.-103T>C		5_prime_UTR	Exon 1 of 5	NP_001050.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TACR3	ENST00000304883.3	TSL:1 MANE Select	c.-103T>C		5_prime_UTR	Exon 1 of 5	ENSP00000303325.2

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51266 AN: 151940 Hom.: 13257 Cov.: 32

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.192 AC: 249952 AN: 1301740 Hom.: 31563 Cov.: 19 AF XY: 0.194 AC XY: 126097 AN XY: 648918

African (AFR) AF: 0.754 AC: 22633 AN: 30008

American (AMR) AF: 0.213 AC: 8039 AN: 37734

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4531 AN: 24402

East Asian (EAS) AF: 0.365 AC: 13196 AN: 36198

South Asian (SAS) AF: 0.339 AC: 26912 AN: 79476

European-Finnish (FIN) AF: 0.165 AC: 5987 AN: 36234

Middle Eastern (MID) AF: 0.272 AC: 1458 AN: 5362

European-Non Finnish (NFE) AF: 0.155 AC: 154755 AN: 997156

Other (OTH) AF: 0.226 AC: 12441 AN: 55170

GnomAD4 genome AF: 0.338 AC: 51369 AN: 152058 Hom.: 13302 Cov.: 32 AF XY: 0.338 AC XY: 25107 AN XY: 74342

African (AFR) AF: 0.726 AC: 30105 AN: 41466

American (AMR) AF: 0.245 AC: 3740 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3472

East Asian (EAS) AF: 0.361 AC: 1858 AN: 5150

South Asian (SAS) AF: 0.344 AC: 1661 AN: 4826

European-Finnish (FIN) AF: 0.176 AC: 1865 AN: 10584

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10650 AN: 67968

Other (OTH) AF: 0.308 AC: 649 AN: 2106

Alfa AF: 0.214 Hom.: 22456

Bravo AF: 0.357

Asia WGS AF: 0.372 AC: 1298 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypogonadotropic hypogonadism 11 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.9
DANN	Benign	0.45
PhyloP100		-1.1
PromoterAI		-0.099	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs3733632; hg19: chr4-104640935;