rs397518453

Positions:

• chr12-54283844-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PP2 PP5_Moderate BP4

The NM_031157.4(HNRNPA1):​c.940G>A​(p.Asp314Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPA1 NM_031157.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.65

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HNRNPA1. . Gene score misZ 2.8218 (greater than the threshold 3.09). Trascript score misZ 4.1111 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• PP5: Variant 12-54283844-G-A is Pathogenic according to our data. Variant chr12-54283844-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65452.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35674444). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPA1	NM_031157.4	c.940G>A	p.Asp314Asn	missense_variant	9/11	ENST00000340913.11	NP_112420.1
HNRNPA1	NM_002136.4	c.784G>A	p.Asp262Asn	missense_variant	8/10		NP_002127.1
HNRNPA1	NR_135167.2	n.866G>A		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPA1	ENST00000340913.11	c.940G>A	p.Asp314Asn	missense_variant	9/11	1	NM_031157.4	ENSP00000341826
	ENST00000553061.1	n.545+6669G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 20 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	.;.;T;T;.;.
Eigen	Benign	0.037
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;D;D;D;T;D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.8	.;.;L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D;N;D;.;N;D
REVEL	Benign	0.26
Sift	Benign	0.12	T;D;T;.;D;T
Sift4G	Benign	0.098	T;T;T;T;T;D
Polyphen		0.0040	B;.;B;.;B;.
Vest4		0.39
MutPred		0.33		.;.;Gain of catalytic residue at S311 (P = 0.0054);.;.;.;
MVP		0.77
MPC		0.48
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.54
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs397518453; hg19: chr12-54677628;