12-54280818-C-T

Variant names:

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

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]

HNRNPA1 links:

ENSG00000258344 (HGNC:):

ENSG00000258344 links:

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
HNRNPA1	NM_031157.4 link	c.11C>T	p.Ser4Leu	missense_variant	Exon 1 of 11	ENST00000340913.11	NP_112420.1	P09651-1A0A024RAZ7
HNRNPA1	NM_002136.4 link	c.11C>T	p.Ser4Leu	missense_variant	Exon 1 of 10		NP_002127.1	P09651-2A0A024RB53
HNRNPA1	NR_135167.2 link	n.93C>T		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPA1	ENST00000340913.11 link	c.11C>T	p.Ser4Leu	missense_variant	Exon 1 of 11	1	NM_031157.4	ENSP00000341826.7		P09651-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

249930

Hom.:

AF XY:

0.00

AC XY:

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:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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.:

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

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

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

LIST_S2

Benign

0.82

.;T;D;T;T;T

M_CAP

Benign

0.072

MetaRNN

Benign

0.39

T;T;T;T;T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.2

M;.;M;.;.;M

PrimateAI

Pathogenic

0.84

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over