10-90857556-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019859.4(HTR7):c.116C>G(p.Pro39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,597,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. P39Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: HTR7 NM_019859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.732

Genes affected

HTR7 (HGNC:5302): (5-hydroxytryptamine receptor 7) The neurotransmitter, serotonin, is thought to play a role in various cognitive and behavioral functions. The serotonin receptor encoded by this gene belongs to the superfamily of G protein-coupled receptors and the gene is a candidate locus for involvement in autistic disorder and other neuropsychiatric disorders. Three splice variants have been identified which encode proteins that differ in the length of their carboxy terminal ends. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12544769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR7	NM_019859.4	c.116C>G	p.Pro39Arg	missense_variant	1/4	ENST00000336152.8
HTR7	NM_000872.5	c.116C>G	p.Pro39Arg	missense_variant	1/3
HTR7	NM_019860.4	c.116C>G	p.Pro39Arg	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR7	ENST00000336152.8	c.116C>G	p.Pro39Arg	missense_variant	1/4	1	NM_019859.4
HTR7	ENST00000277874.10	c.116C>G	p.Pro39Arg	missense_variant	1/3	1		A1
HTR7	ENST00000371719.2	c.116C>G	p.Pro39Arg	missense_variant	1/3	1		P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000242 AC: 5 AN: 206270 Hom.: 0 AF XY: 0.00000877 AC XY: 1 AN XY: 114028

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000353 AC: 51 AN: 1445340 Hom.: 0 Cov.: 32 AF XY: 0.0000348 AC XY: 25 AN XY: 717576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000425

Gnomad4 OTH exome AF: 0.0000503

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000861 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000860 AC: 1

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

Apr 12, 2023

The c.116C>G (p.P39R) alteration is located in exon 1 (coding exon 1) of the HTR7 gene. This alteration results from a C to G substitution at nucleotide position 116, causing the proline (P) at amino acid position 39 to be replaced by an arginine (R). 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	0.067
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	1.1
Dann	Benign	0.96
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.048
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.082
MutPred		0.34		Loss of glycosylation at S43 (P = 0.0874);Loss of glycosylation at S43 (P = 0.0874);Loss of glycosylation at S43 (P = 0.0874);
MVP		0.70
MPC		0.56
ClinPred		0.054	T
GERP RS		-0.67
Varity_R		0.092
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs754591406; hg19: chr10-92617313;