12-54282381-GTT-GT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_031157.4(HNRNPA1):c.491-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,431,734 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 0.000087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

HNRNPA1
NM_031157.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.371

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, 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

HNRNPA1 links:

ENSG00000258344 (HGNC:):

ENSG00000258344 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000869 (13/149524) while in subpopulation EAS AF = 0.000587 (3/5108). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 13 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNRNPA1	NM_031157.4	MANE Select	c.491-3delT	splice_region intron	N/A	NP_112420.1	P09651-1
HNRNPA1	NM_002136.4		c.491-3delT	splice_region intron	N/A	NP_002127.1	P09651-2
HNRNPA1	NR_135167.2		n.573-3delT	splice_region intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.0000870

AC:

AN:

149422

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000586

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000134

Gnomad OTH

AF:

0.000489

GnomAD2 exomes

AF:

0.00117

AC:

189

AN:

161306

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.000275

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.000340

Gnomad EAS exome

AF:

0.00154

Gnomad FIN exome

AF:

0.00104

Gnomad NFE exome

AF:

0.000977

Gnomad OTH exome

AF:

0.00273

GnomAD4 exome

AF:

0.000474

AC:

608

AN:

1282210

Hom.:

Cov.:

AF XY:

0.000447

AC XY:

286

AN XY:

640222

show subpopulations

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

African (AFR)

AF:

0.000679

AC:

AN:

29438

American (AMR)

AF:

0.000989

AC:

AN:

39434

Ashkenazi Jewish (ASJ)

AF:

0.000218

AC:

AN:

22946

East Asian (EAS)

AF:

0.000385

AC:

AN:

36348

South Asian (SAS)

AF:

0.000588

AC:

AN:

76552

European-Finnish (FIN)

AF:

0.000477

AC:

AN:

48240

Middle Eastern (MID)

AF:

0.000380

AC:

AN:

5260

European-Non Finnish (NFE)

AF:

0.000445

AC:

432

AN:

970900

Other (OTH)

AF:

0.000527

AC:

AN:

53092

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.265

Heterozygous variant carriers

194

292

389

486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000869

AC:

AN:

149524

Hom.:

Cov.:

AF XY:

0.0000960

AC XY:

AN XY:

72922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40836

American (AMR)

AF:

0.00

AC:

AN:

14996

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.000587

AC:

AN:

5108

South Asian (SAS)

AF:

0.00

AC:

AN:

4720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000134

AC:

AN:

67100

Other (OTH)

AF:

0.000484

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00603

Hom.:

Bravo

AF:

0.0000793

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.37

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over