Genetic Variant HNRNPA1:c.491-9_491-3dupTTTTTTT (chr12-54282381-G-GTTTTTTT) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_031157.4(HNRNPA1):c.491-9_491-3dupTTTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HNRNPA1
NM_031157.4 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.371

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 20
Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
inclusion body myopathy with Paget disease of bone and frontotemporal dementia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HNRNPA1 links:

ENSG00000258344 (HGNC:):

ENSG00000258344 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08310992 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 0 (no position change), new splice context is: gtttttttttttttttttAGttc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031157.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNRNPA1	NM_031157.4	MANE Select	c.491-9_491-3dupTTTTTTT	splice_acceptor intron	N/A	NP_112420.1	P09651-1
HNRNPA1	NM_002136.4		c.491-9_491-3dupTTTTTTT	splice_acceptor intron	N/A	NP_002127.1	P09651-2
HNRNPA1	NR_135167.2		n.573-9_573-3dupTTTTTTT	splice_acceptor intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNRNPA1	ENST00000340913.11	TSL:1 MANE Select	c.491-13_491-12insTTTTTTT	intron	N/A	ENSP00000341826.7	P09651-1
HNRNPA1	ENST00000546500.5	TSL:1	c.491-13_491-12insTTTTTTT	intron	N/A	ENSP00000448617.1	P09651-2
HNRNPA1	ENST00000547276.5	TSL:1	c.491-13_491-12insTTTTTTT	intron	N/A	ENSP00000447260.1	P09651-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

161306

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1291948

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

644804

African (AFR)

AF:

0.00

AC:

AN:

29650

American (AMR)

AF:

0.00

AC:

AN:

39810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23094

East Asian (EAS)

AF:

0.00

AC:

AN:

36418

South Asian (SAS)

AF:

0.00

AC:

AN:

77072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5274

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

978622

Other (OTH)

AF:

0.00

AC:

AN:

53448

GnomAD4 genome

Cov.:

Alfa

AF:

0.000217

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.37

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-54282381-GTT-GTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over