rs74625894

chr12-54281778-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_031157.4(HNRNPA1):c.133-17A>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.929

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 261941.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-54281778-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 440 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPA1	NM_031157.4	c.133-17A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000340913.11
HNRNPA1	NM_002136.4	c.133-17A>G		splice_polypyrimidine_tract_variant, intron_variant
HNRNPA1	NR_135167.2	n.215-17A>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPA1	ENST00000340913.11	c.133-17A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_031157.4
	ENST00000553061.1	n.545+4603A>G		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.00262 AC: 638 AN: 243232 Hom.: 3 AF XY: 0.00260 AC XY: 344 AN XY: 132348

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 SAS exome AF: 0.00111

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

Gnomad4 AFR exome AF: 0.000667

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.00151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00484

Gnomad4 OTH exome AF: 0.00459

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

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00811

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00388

Gnomad4 OTH AF: 0.00237

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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	11
Dann	Benign	0.79

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

LitVar

Other links and lift over

dbSNP: rs74625894; hg19: chr12-54675562;