12-54282381-G-GT

Variant names:

• chr12-54282381-G-GT
• rs202119045
• NM_031157.4:c.491-3dupT

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -8 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 9.7, 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 396 AD gene.

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.491-3dupT		splice_acceptor intron	N/A	NP_112420.1	P09651-1
	HNRNPA1	NM_002136.4		c.491-3dupT		splice_acceptor intron	N/A	NP_002127.1	P09651-2
	HNRNPA1	NR_135167.2		n.573-3dupT		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_491-12insT		intron	N/A	ENSP00000341826.7	P09651-1
	HNRNPA1	ENST00000546500.5	TSL:1	c.491-13_491-12insT		intron	N/A	ENSP00000448617.1	P09651-2
	HNRNPA1	ENST00000547276.5	TSL:1	c.491-13_491-12insT		intron	N/A	ENSP00000447260.1	P09651-3

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

GnomAD2 exomes AF: 0.00379 AC: 612 AN: 161306 AF XY: 0.00311

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00806

Gnomad FIN exome AF: 0.00588

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00382

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

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

African (AFR) AF: 0.0128 AC: 355 AN: 27694

American (AMR) AF: 0.00267 AC: 99 AN: 37058

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 58 AN: 21334

East Asian (EAS) AF: 0.00322 AC: 110 AN: 34194

South Asian (SAS) AF: 0.00260 AC: 185 AN: 71260

European-Finnish (FIN) AF: 0.00240 AC: 110 AN: 45784

Middle Eastern (MID) AF: 0.00159 AC: 8 AN: 5018

European-Non Finnish (NFE) AF: 0.00546 AC: 4965 AN: 909412

Other (OTH) AF: 0.00468 AC: 233 AN: 49780

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00872 AC: 356 AN: 40828

American (AMR) AF: 0.000533 AC: 8 AN: 14996

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

East Asian (EAS) AF: 0.00489 AC: 25 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4722

European-Finnish (FIN) AF: 0.000199 AC: 2 AN: 10062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000596 AC: 4 AN: 67096

Other (OTH) AF: 0.000484 AC: 1 AN: 2064

Alfa AF: 0.0241 Hom.: 0

Bravo AF: 0.00312

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Amyotrophic lateral sclerosis type 20;C3809469:Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs202119045; hg19: chr12-54676165; COSMIC: COSV104393092; COSMIC: COSV104393092;