rs74625894

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 0.929

Publications

0 publications found

Variant links:

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

HNRNPA1 links:

ENSG00000258344 (HGNC:):

ENSG00000258344 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
HNRNPA1	NM_031157.4 link	c.133-17A>G	intron_variant	Intron 2 of 10	ENST00000340913.11	NP_112420.1
HNRNPA1	NM_002136.4 link	c.133-17A>G	intron_variant	Intron 2 of 9		NP_002127.1
HNRNPA1	NR_135167.2 link	n.215-17A>G	intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPA1	ENST00000340913.11 link	c.133-17A>G		intron_variant	Intron 2 of 10	1	NM_031157.4	ENSP00000341826.7

Frequencies

GnomAD3 genomes

AF:

0.00289

AC:

440

AN:

152166

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00396

AC XY:

2867

AN XY:

723350

show subpopulations

African (AFR)

AF:

0.000667

AC:

AN:

33002

American (AMR)

AF:

0.00463

AC:

198

AN:

42802

Ashkenazi Jewish (ASJ)

AF:

0.00151

AC:

AN:

25836

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00111

AC:

AN:

85462

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.000422

AC:

AN:

4734

European-Non Finnish (NFE)

AF:

0.00484

AC:

5370

AN:

1109502

Other (OTH)

AF:

0.00459

AC:

275

AN:

59964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

260

521

781

1042

1302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

230

460

690

920

1150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00289

AC:

440

AN:

152284

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41554

American (AMR)

AF:

0.00811

AC:

124

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00388

AC:

264

AN:

68020

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00233

Hom.:

Bravo

AF:

0.00316

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

0.93

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over