Genetic Variant PRLHR:p.Thr233Ile (chr10-118594547-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004248.3(PRLHR):c.698C>T(p.Thr233Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000511 in 1,565,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

PRLHR
NM_004248.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.02

Publications

0 publications found

Variant links:

Genes affected

PRLHR (HGNC:4464): (prolactin releasing hormone receptor) Predicted to enable neuropeptide receptor activity. Predicted to be involved in female pregnancy. Predicted to act upstream of or within G protein-coupled receptor signaling pathway; feeding behavior; and hormone metabolic process. Located in cilium. Implicated in hypertension. [provided by Alliance of Genome Resources, Apr 2022]

PRLHR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRLHR	NM_004248.3 link	c.698C>T	p.Thr233Ile	missense_variant	Exon 2 of 2	ENST00000239032.4	NP_004239.2	P49683A5JUU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRLHR	ENST00000239032.4 link	c.698C>T	p.Thr233Ile	missense_variant	Exon 2 of 2	1	NM_004248.3	ENSP00000239032.2		P49683
PRLHR	ENST00000636925.1 link	c.698C>T	p.Thr233Ile	missense_variant	Exon 1 of 1	6		ENSP00000490073.1		P49683

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

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

GnomAD4 exome

AF:

0.00000354

AC:

AN:

1413630

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698756

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32356

American (AMR)

AF:

0.00

AC:

AN:

38172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25300

East Asian (EAS)

AF:

0.00

AC:

AN:

37100

South Asian (SAS)

AF:

0.00

AC:

AN:

82058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000460

AC:

AN:

1087596

Other (OTH)

AF:

0.00

AC:

AN:

58582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000197

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.698C>T (p.T233I) alteration is located in exon 2 (coding exon 1) of the PRLHR gene. This alteration results from a C to T substitution at nucleotide position 698, causing the threonine (T) at amino acid position 233 to be replaced by an isoleucine (I). 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

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.82

.;T

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.85

L;L

PhyloP100

5.0

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.8

D;.

REVEL

Uncertain

0.60

Sift

Uncertain

0.012

D;.

Sift4G

Benign

0.30

T;.

Polyphen

1.0

D;D

Vest4

0.36

MutPred

0.78

Gain of catalytic residue at L238 (P = 0.0786);Gain of catalytic residue at L238 (P = 0.0786);

MVP

0.86

MPC

1.1

ClinPred

0.98

GERP RS

3.8

Varity_R

0.48

gMVP

0.45

Mutation Taster

=80/20

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over