rs202119045

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-54282381-GTT-G
• chr12-54282381-GTT-GT
• chr12-54282381-GTT-GTTT
• chr12-54282381-GTT-GTTTT
• chr12-54282381-GTT-GTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031157.4(HNRNPA1):​c.491-4_491-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000669 in 149,448 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HNRNPA1 NM_031157.4 splice_region, 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 2 ACMG points.

• 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_491-3delTT		splice_region intron	N/A	NP_112420.1	P09651-1
	HNRNPA1	NM_002136.4		c.491-4_491-3delTT		splice_region intron	N/A	NP_002127.1	P09651-2
	HNRNPA1	NR_135167.2		n.573-4_573-3delTT		splice_region intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00000669 AC: 1 AN: 149448 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1291890 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 644776

African (AFR) AF: 0.00 AC: 0 AN: 29650

American (AMR) AF: 0.00 AC: 0 AN: 39806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23094

East Asian (EAS) AF: 0.00 AC: 0 AN: 36418

South Asian (SAS) AF: 0.00 AC: 0 AN: 77070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48552

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 978580

Other (OTH) AF: 0.00 AC: 0 AN: 53446

GnomAD4 genome AF: 0.00000669 AC: 1 AN: 149448 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72828

African (AFR) AF: 0.00 AC: 0 AN: 40728

American (AMR) AF: 0.00 AC: 0 AN: 14980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67116

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs202119045; hg19: chr12-54676165; COSMIC: COSV52937018; COSMIC: COSV52937018;