12-54282381-G-GT

Position:

• chr12-54282381-G-GT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BS1 BS2

The NM_031157.4(HNRNPA1):​c.491-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,351,046 control chromosomes in the GnomAD database, including 4 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (0 hom.)
• Consequence: HNRNPA1 NM_031157.4 splice_acceptor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.371

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08221626 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.7, offset of 0 (no position change), new splice context is: atctatgtttttttttttAGttc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 12-54282381-G-GT is Benign according to our data. Variant chr12-54282381-G-GT is described in ClinVar as [Likely_benign]. Clinvar id is 1209889.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00265 (396/149512) while in subpopulation AFR AF= 0.00872 (356/40828). AF 95% confidence interval is 0.00797. There are 4 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 396 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPA1	NM_031157.4	c.491-3dupT		splice_acceptor_variant, intron_variant		ENST00000340913.11	NP_112420.1
HNRNPA1	NM_002136.4	c.491-3dupT		splice_acceptor_variant, intron_variant			NP_002127.1
HNRNPA1	NR_135167.2	n.573-3dupT		splice_acceptor_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPA1	ENST00000340913.11	c.491-3dupT		splice_acceptor_variant, intron_variant		1	NM_031157.4	ENSP00000341826.7

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 396 AN: 149408 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000534

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00488

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000199

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000596

Gnomad OTH AF: 0.000489

GnomAD4 exome AF: 0.00510 AC: 6123 AN: 1201534 Hom.: 0 Cov.: 31 AF XY: 0.00457 AC XY: 2740 AN XY: 599726

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.00267

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.00322

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.00546

Gnomad4 OTH exome AF: 0.00468

GnomAD4 genome AF: 0.00265 AC: 396 AN: 149512 Hom.: 4 Cov.: 32 AF XY: 0.00237 AC XY: 173 AN XY: 72918

Gnomad4 AFR AF: 0.00872

Gnomad4 AMR AF: 0.000533

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00489

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000199

Gnomad4 NFE AF: 0.0000596

Gnomad4 OTH AF: 0.000484

Bravo AF: 0.00312

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Amyotrophic lateral sclerosis type 20;C3809469:Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs202119045; hg19: chr12-54676165;