Genetic Variant NM_000524.4:c.-480delA (chr5-63962198-CT-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000524.4(HTR1A):c.-480delA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 217,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

HTR1A
NM_000524.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1

Conservation

PhyloP100: -0.0570

Publications

3 publications found

Variant links:

Genes affected

HTR1A (HGNC:5286): (5-hydroxytryptamine receptor 1A) This gene encodes a G protein-coupled receptor for 5-hydroxytryptamine (serotonin), and belongs to the 5-hydroxytryptamine receptor subfamily. Serotonin has been implicated in a number of physiologic processes and pathologic conditions. Inactivation of this gene in mice results in behavior consistent with an increased anxiety and stress response. Mutation in the promoter of this gene has been associated with menstrual cycle-dependent periodic fevers. [provided by RefSeq, Jun 2012]

HTR1A Gene-Disease associations (from GenCC):

menstrual cycle-dependent periodic fever
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

HTR1A links:

ENSG00000248285 (HGNC:):

ENSG00000248285 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 5-63962198-CT-C is Benign according to our data. Variant chr5-63962198-CT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31658.

BS2

High AC in GnomAd4 at 47 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000524.4. 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
	HTR1A	NM_000524.4	MANE Select	c.-480delA		5_prime_UTR	Exon 1 of 1	NP_000515.2	P08908

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HTR1A	ENST00000323865.5	TSL:6 MANE Select	c.-480delA	5_prime_UTR	Exon 1 of 1	ENSP00000316244.4	P08908
HTR1A	ENST00000506598.1	TSL:4	c.-387-93delA	intron	N/A	ENSP00000423433.1	D6RA34
ENSG00000248285	ENST00000502882.1	TSL:2	n.97-4184delA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000310

AC:

AN:

151634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00838

Gnomad SAS

AF:

0.000627

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000380

AC:

AN:

65828

Hom.:

AF XY:

0.000348

AC XY:

AN XY:

34444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

1610

American (AMR)

AF:

0.00

AC:

AN:

3798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1380

East Asian (EAS)

AF:

0.00646

AC:

AN:

3252

South Asian (SAS)

AF:

0.000410

AC:

AN:

9764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

39502

Other (OTH)

AF:

0.00

AC:

AN:

3392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000310

AC:

AN:

151752

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.0000656

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00840

AC:

AN:

5118

South Asian (SAS)

AF:

0.000627

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67868

Other (OTH)

AF:

0.00

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000843

Hom.:

Bravo

AF:

0.000295

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Menstrual cycle-dependent periodic fever (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.057

Splicing

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