12-54282381-GTT-GTTTT

Variant names:

• chr12-54282381-G-GTT
• rs202119045
• NM_031157.4:c.491-4_491-3dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_031157.4(HNRNPA1):​c.491-4_491-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000232 in 1,291,598 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: HNRNPA1 NM_031157.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.371
• Publications: 0 publications found

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

ENSG00000258344 (HGNC:):

ACMG classification

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 9.6, offset of 0 (no position change), new splice context is: tctatgttttttttttttAGttc. 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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000232 AC: 3 AN: 1291598 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 644648

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29644

American (AMR) AF: 0.00 AC: 0 AN: 39810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23090

East Asian (EAS) AF: 0.00 AC: 0 AN: 36416

South Asian (SAS) AF: 0.00 AC: 0 AN: 77064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5274

European-Non Finnish (NFE) AF: 0.00000307 AC: 3 AN: 978314

Other (OTH) AF: 0.00 AC: 0 AN: 53438

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000647710), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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

Other links and lift over

dbSNP: rs202119045; hg19: chr12-54676165;