NM_006261.5:c.152G>T
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1
The NM_006261.5(PROP1):c.152G>T(p.Gly51Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,611,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G51A) has been classified as Benign.
Frequency
Consequence
NM_006261.5 missense
Scores
Clinical Significance
Conservation
Publications
- pituitary hormone deficiency, combined, 2Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- combined pituitary hormone deficiencies, genetic formInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hypothyroidism due to deficient transcription factors involved in pituitary development or functionInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- panhypopituitarismInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PROP1 | NM_006261.5 | c.152G>T | p.Gly51Val | missense_variant | Exon 2 of 3 | ENST00000308304.2 | NP_006252.4 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152114Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.000222 AC: 54AN: 243052 AF XY: 0.000227 show subpopulations
GnomAD4 exome AF: 0.0000589 AC: 86AN: 1459246Hom.: 0 Cov.: 32 AF XY: 0.0000565 AC XY: 41AN XY: 725598 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152232Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6AN XY: 74434 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
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In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36268624, 32319661) -
not specified Uncertain:1
Variant summary: PROP1 c.152G>T (p.Gly51Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.2e-05 in 1611478 control chromosomes, predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PROP1 causing Combined Pituitary Hormone Deficiency (6.2e-05 vs 0.0041), allowing no conclusion about variant significance. c.152G>T has been reported in the literature in individuals affected with Congenital hypothyroidism (Wang_2020). This report, however, does not provide unequivocal conclusions about association of the variant with Combined Pituitary Hormone Deficiency. Co-occurrence with other pathogenic variant has been reported (a 400 bp deletion of ANOS1), providing supporting evidence for a benign role (Dwyer_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36268624, 32319661). ClinVar contains an entry for this variant (Variation ID: 742937). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Pituitary hormone deficiency, combined, 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at