10-90743643-G-C

Position:

• chr10-90743643-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019859.4(HTR7):​c.1343C>G​(p.Pro448Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,613,886 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P448Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (79 hom.)
• Consequence: HTR7 NM_019859.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.12

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002271235).
• BP6: Variant 10-90743643-G-C is Benign according to our data. Variant chr10-90743643-G-C is described in ClinVar as [Benign]. Clinvar id is 778468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR7	NM_019859.4	c.1343C>G	p.Pro448Arg	missense_variant	3/4	ENST00000336152.8
HTR7	XM_024447973.2	c.749C>G	p.Pro250Arg	missense_variant	3/4
HTR7	NM_000872.5	c.1296-1115C>G		intron_variant
HTR7	NM_019860.4	c.*2-1115C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR7	ENST00000336152.8	c.1343C>G	p.Pro448Arg	missense_variant	3/4	1	NM_019859.4
HTR7	ENST00000277874.10	c.1296-1115C>G		intron_variant		1		A1
HTR7	ENST00000371719.2	c.*2-1115C>G		intron_variant		1		P4

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2670 AN: 152080 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00911

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00769

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00741 AC: 1862 AN: 251380 Hom.: 26 AF XY: 0.00669 AC XY: 909 AN XY: 135856

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.0326

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00470

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00332

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00542 AC: 7923 AN: 1461688 Hom.: 79 Cov.: 31 AF XY: 0.00530 AC XY: 3851 AN XY: 727144

Gnomad4 AFR exome AF: 0.0522

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.0298

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.00472

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00374

Gnomad4 OTH exome AF: 0.00898

GnomAD4 genome AF: 0.0176 AC: 2673 AN: 152198 Hom.: 56 Cov.: 32 AF XY: 0.0166 AC XY: 1234 AN XY: 74416

Gnomad4 AFR AF: 0.0499

Gnomad4 AMR AF: 0.00910

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00748

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00391

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00558 Hom.: 6

Bravo AF: 0.0193

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.0490 AC: 216

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00826 AC: 1003

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0060
DANN	Benign	0.20
DEOGEN2	Benign	0.12	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.00062	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.026
Sift	Benign	0.46	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.089
MVP		0.47
MPC		0.44
ClinPred		0.00064	T
GERP RS		-3.8
Varity_R		0.033
gMVP		0.11

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: rs33954285; hg19: chr10-92503400;