chr12-54281778-A-G

Variant names:

• chr12-54281778-A-G
• rs74625894
• NM_031157.4:c.133-17A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_031157.4(HNRNPA1):​c.133-17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,606,530 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (16 hom.)
• Consequence: HNRNPA1 NM_031157.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.929
• 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 Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-54281778-A-G is Benign according to our data. Variant chr12-54281778-A-G is described in ClinVar as Benign. ClinVar VariationId is 261941.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00289 (440/152284) while in subpopulation AMR AF = 0.00811 (124/15292). AF 95% confidence interval is 0.00695. There are 1 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 440 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA1	NM_031157.4	MANE Select	c.133-17A>G		intron	N/A	NP_112420.1
	HNRNPA1	NM_002136.4		c.133-17A>G		intron	N/A	NP_002127.1
	HNRNPA1	NR_135167.2		n.215-17A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA1	ENST00000340913.11	TSL:1 MANE Select	c.133-17A>G		intron	N/A	ENSP00000341826.7
	HNRNPA1	ENST00000546500.5	TSL:1	c.133-17A>G		intron	N/A	ENSP00000448617.1
	HNRNPA1	ENST00000547276.5	TSL:1	c.133-17A>G		intron	N/A	ENSP00000447260.1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00262 AC: 638 AN: 243232 AF XY: 0.00260

Gnomad AFR exome AF: 0.000784

Gnomad AMR exome AF: 0.00479

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.00413 AC: 6013 AN: 1454246 Hom.: 16 Cov.: 32 AF XY: 0.00396 AC XY: 2867 AN XY: 723350

African (AFR) AF: 0.000667 AC: 22 AN: 33002

American (AMR) AF: 0.00463 AC: 198 AN: 42802

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 39 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00111 AC: 95 AN: 85462

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53316

Middle Eastern (MID) AF: 0.000422 AC: 2 AN: 4734

European-Non Finnish (NFE) AF: 0.00484 AC: 5370 AN: 1109502

Other (OTH) AF: 0.00459 AC: 275 AN: 59964

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74464

African (AFR) AF: 0.000890 AC: 37 AN: 41554

American (AMR) AF: 0.00811 AC: 124 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00388 AC: 264 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00233 Hom.: 0

Bravo AF: 0.00316

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		0.93
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74625894; hg19: chr12-54675562;