10-90857475-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_019859.4(HTR7):c.197A>G(p.Asn66Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: HTR7 NM_019859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.02

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 2 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity 5HT7R_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17478874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR7	NM_019859.4	c.197A>G	p.Asn66Ser	missense_variant	1/4	ENST00000336152.8
HTR7	NM_000872.5	c.197A>G	p.Asn66Ser	missense_variant	1/3
HTR7	NM_019860.4	c.197A>G	p.Asn66Ser	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR7	ENST00000336152.8	c.197A>G	p.Asn66Ser	missense_variant	1/4	1	NM_019859.4
HTR7	ENST00000277874.10	c.197A>G	p.Asn66Ser	missense_variant	1/3	1		A1
HTR7	ENST00000371719.2	c.197A>G	p.Asn66Ser	missense_variant	1/3	1		P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247322 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134438

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

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: 0.00000821 AC: 12 AN: 1461420 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

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 20, 2023

The c.197A>G (p.N66S) alteration is located in exon 1 (coding exon 1) of the HTR7 gene. This alteration results from a A to G substitution at nucleotide position 197, causing the asparagine (N) at amino acid position 66 to be replaced by a serine (S). 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	0.086
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.092
Sift	Benign	0.096	T;T;T
Sift4G	Uncertain	0.034	D;D;D
Polyphen		0.010	B;B;.
Vest4		0.30
MutPred		0.33		Gain of glycosylation at N66 (P = 0.0012);Gain of glycosylation at N66 (P = 0.0012);Gain of glycosylation at N66 (P = 0.0012);
MVP		0.76
MPC		0.33
ClinPred		0.25	T
GERP RS		2.8
Varity_R		0.21
gMVP		0.46

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: rs761782243; hg19: chr10-92617232;