chr17-81891576-G-T
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2
The NM_005782.4(ALYREF):c.5C>A(p.Pro2His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000085 in 1,435,740 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00051 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000035 ( 1 hom. )
Consequence
ALYREF
NM_005782.4 missense
NM_005782.4 missense
Scores
3
1
13
Clinical Significance
Conservation
PhyloP100: 2.17
Genes affected
ALYREF (HGNC:19071): (Aly/REF export factor) The protein encoded by this gene is a heat stable, nuclear protein and functions as a molecular chaperone. It is thought to regulate dimerization, DNA binding, and transcriptional activity of basic region-leucine zipper (bZIP) proteins. [provided by RefSeq, Jul 2008]
ANAPC11 (HGNC:14452): (anaphase promoting complex subunit 11) Enables cullin family protein binding activity and ubiquitin-ubiquitin ligase activity. Contributes to ubiquitin-protein transferase activity. Involved in protein K11-linked ubiquitination. Located in nucleolus and nucleoplasm. Part of anaphase-promoting complex. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PM1
In a modified_residue N-acetylalanine (size 0) in uniprot entity THOC4_HUMAN
BP4
Computational evidence support a benign effect (MetaRNN=0.012083739).
BS2
High AC in GnomAd4 at 77 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALYREF | NM_005782.4 | c.5C>A | p.Pro2His | missense_variant | 1/6 | ENST00000505490.3 | |
ANAPC11 | NM_001289414.1 | c.-75+725G>T | intron_variant | ||||
ALYREF | NR_158770.1 | n.12C>A | non_coding_transcript_exon_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALYREF | ENST00000505490.3 | c.5C>A | p.Pro2His | missense_variant | 1/6 | 1 | NM_005782.4 | P1 | |
ANAPC11 | ENST00000571570.5 | c.-75+725G>T | intron_variant | 3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000508 AC: 77AN: 151544Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000385 AC: 3AN: 77922Hom.: 0 AF XY: 0.0000223 AC XY: 1AN XY: 44902
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GnomAD4 exome AF: 0.0000350 AC: 45AN: 1284088Hom.: 1 Cov.: 31 AF XY: 0.0000363 AC XY: 23AN XY: 633348
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GnomAD4 genome AF: 0.000508 AC: 77AN: 151652Hom.: 0 Cov.: 31 AF XY: 0.000364 AC XY: 27AN XY: 74082
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
ALYREF-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 22, 2023 | The ALYREF c.5C>A variant is predicted to result in the amino acid substitution p.Pro2His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.18% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-79849452-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
D;N;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
B
Vest4
MutPred
Loss of catalytic residue at P2 (P = 0.011);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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