12-54280818-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1PM2PP2BP4BS2

The NM_031157.4(HNRNPA1):​c.11C>T​(p.Ser4Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,876 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HNRNPA1
NM_031157.4 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.81
Variant links:
Genes affected
HNRNPA1 (HGNC:5031): (heterogeneous nuclear ribonucleoprotein A1) This gene encodes a member of a family of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs), which are RNA-binding proteins that associate with pre-mRNAs in the nucleus and influence pre-mRNA processing, as well as other aspects of mRNA metabolism and transport. The protein encoded by this gene is one of the most abundant core proteins of hnRNP complexes and plays a key role in the regulation of alternative splicing. Mutations in this gene have been observed in individuals with amyotrophic lateral sclerosis 20. Multiple alternatively spliced transcript variants have been found. There are numerous pseudogenes of this gene distributed throughout the genome. [provided by RefSeq, Feb 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity ROA1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the HNRNPA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.8218 (below the threshold of 3.09). Trascript score misZ: 4.1111 (above the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3, amyotrophic lateral sclerosis type 20.
BP4
Computational evidence support a benign effect (MetaRNN=0.39346075).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNRNPA1NM_031157.4 linkc.11C>T p.Ser4Leu missense_variant Exon 1 of 11 ENST00000340913.11 NP_112420.1 P09651-1A0A024RAZ7
HNRNPA1NM_002136.4 linkc.11C>T p.Ser4Leu missense_variant Exon 1 of 10 NP_002127.1 P09651-2A0A024RB53
HNRNPA1NR_135167.2 linkn.93C>T non_coding_transcript_exon_variant Exon 1 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNRNPA1ENST00000340913.11 linkc.11C>T p.Ser4Leu missense_variant Exon 1 of 11 1 NM_031157.4 ENSP00000341826.7 P09651-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
249930
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135572
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461876
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
May 13, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
.;.;T;T;T;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.82
.;T;D;T;T;T
M_CAP
Benign
0.072
D
MetaRNN
Benign
0.39
T;T;T;T;T;T
MetaSVM
Uncertain
0.51
D
MutationAssessor
Uncertain
2.2
M;.;M;.;.;M
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-2.9
D;D;D;D;D;D
REVEL
Uncertain
0.49
Sift
Benign
0.081
T;D;T;T;T;T
Sift4G
Benign
0.073
T;D;T;T;T;T
Polyphen
0.84
P;.;P;.;P;B
Vest4
0.38
MutPred
0.26
Loss of phosphorylation at S4 (P = 0.0028);Loss of phosphorylation at S4 (P = 0.0028);Loss of phosphorylation at S4 (P = 0.0028);Loss of phosphorylation at S4 (P = 0.0028);Loss of phosphorylation at S4 (P = 0.0028);Loss of phosphorylation at S4 (P = 0.0028);
MVP
0.78
MPC
1.7
ClinPred
0.95
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.25
gMVP
0.61

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1256552845; hg19: chr12-54674602; API