Genetic Variant HTR7:p.Pro448Arg (chr10-90743643-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 56 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 79 hom. )

Consequence

HTR7
NM_019859.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.12

Publications

10 publications found

Variant links:

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]

HTR7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019859.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HTR7	NM_019859.4	MANE Select	c.1343C>G	p.Pro448Arg	missense	Exon 3 of 4	NP_062873.1	P34969-1
HTR7	NM_000872.5		c.1296-1115C>G		intron	N/A	NP_000863.1	P34969-2
HTR7	NM_019860.4		c.*2-1115C>G		intron	N/A	NP_062874.1	P34969-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HTR7	ENST00000336152.8	TSL:1 MANE Select	c.1343C>G	p.Pro448Arg	missense	Exon 3 of 4	ENSP00000337949.3	P34969-1
HTR7	ENST00000277874.10	TSL:1	c.1296-1115C>G		intron	N/A	ENSP00000277874.6	P34969-2
HTR7	ENST00000371719.2	TSL:1	c.*2-1115C>G		intron	N/A	ENSP00000360784.2	P34969-3

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2670

AN:

152080

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00741

AC:

1862

AN:

251380

AF XY:

0.00669

show subpopulations

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 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.:

Cov.:

AF XY:

0.00530

AC XY:

3851

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.0522

AC:

1746

AN:

33462

American (AMR)

AF:

0.00483

AC:

216

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0298

AC:

779

AN:

26128

East Asian (EAS)

AF:

0.000378

AC:

AN:

39698

South Asian (SAS)

AF:

0.00472

AC:

407

AN:

86256

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00374

AC:

4157

AN:

1111862

Other (OTH)

AF:

0.00898

AC:

542

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

403

807

1210

1614

2017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0176

AC:

2673

AN:

152198

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1234

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0499

AC:

2073

AN:

41522

American (AMR)

AF:

0.00910

AC:

139

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

118

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00748

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00391

AC:

266

AN:

68008

Other (OTH)

AF:

0.0137

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00558

Hom.:

Bravo

AF:

0.0193

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.0490

AC:

216

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00826

AC:

1003

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0060

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.12

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.00062

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-2.1

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.28

REVEL

Benign

0.026

Sift

Benign

0.46

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.089

MVP

0.47

MPC

0.44

ClinPred

0.00064

GERP RS

-3.8

Varity_R

0.033

gMVP

0.11

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over