chr3-57198476-T-C
Variant summary
Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_003865.3(HESX1):c.374A>G(p.Asn125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,589,044 control chromosomes in the GnomAD database, including 2,249 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N125G) has been classified as Uncertain significance.
Frequency
Consequence
NM_003865.3 missense
Scores
Clinical Significance
Conservation
Publications
- septooptic dysplasiaInheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
- 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
- Kallmann syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- pituitary stalk interruption syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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HESX1 | ENST00000295934.8 | c.374A>G | p.Asn125Ser | missense_variant | Exon 3 of 4 | 1 | NM_003865.3 | ENSP00000295934.3 | ||
HESX1 | ENST00000647958.1 | c.374A>G | p.Asn125Ser | missense_variant | Exon 6 of 7 | ENSP00000498190.1 | ||||
HESX1 | ENST00000473921.2 | c.358-181A>G | intron_variant | Intron 2 of 2 | 5 | ENSP00000418918.1 |
Frequencies
GnomAD3 genomes AF: 0.0696 AC: 10584AN: 152130Hom.: 1240 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0179 AC: 4419AN: 247290 AF XY: 0.0131 show subpopulations
GnomAD4 exome AF: 0.00697 AC: 10019AN: 1436796Hom.: 1004 Cov.: 27 AF XY: 0.00606 AC XY: 4342AN XY: 716234 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0698 AC: 10624AN: 152248Hom.: 1245 Cov.: 32 AF XY: 0.0690 AC XY: 5137AN XY: 74450 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Benign:4
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This variant is associated with the following publications: (PMID: 11748154, 19844116, 20981092, 21228398, 10599689, 27884173, 27013732, 25910213) -
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not specified Benign:2
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Combined Pituitary Hormone Deficiency, Dominant/Recessive Benign:1
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Septo-optic dysplasia sequence;C2750027:GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES Benign:1
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Septo-optic dysplasia sequence Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at