chr14-94304471-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_001756.4(SERPINA6):c.1165G>A(p.Asp389Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000358 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 0 hom. )
Consequence
SERPINA6
NM_001756.4 missense
NM_001756.4 missense
Scores
1
8
9
Clinical Significance
Conservation
PhyloP100: 3.96
Genes affected
SERPINA6 (HGNC:1540): (serpin family A member 6) This gene encodes an alpha-globulin protein with corticosteroid-binding properties. This is the major transport protein for glucorticoids and progestins in the blood of most vertebrates. The gene localizes to a chromosomal region containing several closely related serine protease inhibitors which may have evolved by duplication events. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-94304471-C-T is Pathogenic according to our data. Variant chr14-94304471-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16975.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr14-94304471-C-T is described in UniProt as null. Variant chr14-94304471-C-T is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.013436496).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINA6 | NM_001756.4 | c.1165G>A | p.Asp389Asn | missense_variant | 5/5 | ENST00000341584.4 | |
SERPINA6 | XM_047431827.1 | c.1336G>A | p.Asp446Asn | missense_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINA6 | ENST00000341584.4 | c.1165G>A | p.Asp389Asn | missense_variant | 5/5 | 1 | NM_001756.4 | P1 | |
SERPINA6 | ENST00000555056.1 | c.*477G>A | 3_prime_UTR_variant, NMD_transcript_variant | 5/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000507 AC: 77AN: 152000Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000617 AC: 155AN: 251322Hom.: 0 AF XY: 0.000567 AC XY: 77AN XY: 135852
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GnomAD4 exome AF: 0.000343 AC: 501AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.000355 AC XY: 258AN XY: 727248
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GnomAD4 genome ? AF: 0.000506 AC: 77AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35AN XY: 74368
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Corticosteroid-binding globulin deficiency Pathogenic:3Uncertain:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital | Jan 30, 2020 | - - |
Likely pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_001756.3:c.1165G>A in the SERPINA6 gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. It was detected in individual with autosomal recessive Corticosteroid-binding globulin deficiency, two homozygous c.1165G>A(PMID: 12780753; 20610591). Co-segregation evidence in a pedigree, two patients were affected and one sibling unaffected (PMID: 20610591). Pathogenic computational verdict because 9 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster and REVEL. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PP1_Moderate; PM3; PP4; PP3. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 26, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at