12-54283845-A-G

Position:

• chr12-54283845-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_031157.4(HNRNPA1):​c.941A>G​(p.Asp314Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPA1 NM_031157.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPA1	NM_031157.4	c.941A>G	p.Asp314Gly	missense_variant	9/11	ENST00000340913.11	NP_112420.1
HNRNPA1	NM_002136.4	c.785A>G	p.Asp262Gly	missense_variant	8/10		NP_002127.1
HNRNPA1	NR_135167.2	n.867A>G		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPA1	ENST00000340913.11	c.941A>G	p.Asp314Gly	missense_variant	9/11	1	NM_031157.4	ENSP00000341826
	ENST00000553061.1	n.545+6670A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;T;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;T;T;D;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.8	.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D;N;D;.;N;D
REVEL	Uncertain	0.53
Sift	Benign	0.088	T;D;D;.;T;T
Sift4G	Benign	0.22	T;T;T;T;T;T
Polyphen		0.59	P;.;B;.;B;.
Vest4		0.73
MutPred		0.37		.;.;Gain of catalytic residue at S311 (P = 0.0019);.;.;.;
MVP		0.82
MPC		0.65
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397518452; hg19: chr12-54677629;