chr12-54284196-C-T

Variant names:

• chr12-54284196-C-T
• rs7967622
• NM_031157.4:c.1064-62C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031157.4(HNRNPA1):​c.1064-62C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,545,004 control chromosomes in the GnomAD database, including 384,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45827 hom., cov: 33)
  • Exomes 𝑓: 0.69 (338255 hom.)
• Consequence: HNRNPA1 NM_031157.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.426
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-54284196-C-T is Benign according to our data. Variant chr12-54284196-C-T is described in ClinVar as Benign. ClinVar VariationId is 1226405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

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.1064-62C>T		intron	N/A	NP_112420.1
	HNRNPA1	NM_002136.4		c.908-62C>T		intron	N/A	NP_002127.1
	HNRNPA1	NR_135167.2		n.990-62C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA1	ENST00000340913.11	TSL:1 MANE Select	c.1064-62C>T		intron	N/A	ENSP00000341826.7
	HNRNPA1	ENST00000546500.5	TSL:1	c.908-62C>T		intron	N/A	ENSP00000448617.1
	HNRNPA1	ENST00000547276.5	TSL:1	c.749-62C>T		intron	N/A	ENSP00000447260.1

Frequencies

GnomAD3 genomes AF: 0.763 AC: 116054 AN: 152094 Hom.: 45758 Cov.: 33

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.885

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.727

GnomAD4 exome AF: 0.690 AC: 961060 AN: 1392792 Hom.: 338255 Cov.: 21 AF XY: 0.692 AC XY: 481631 AN XY: 695560

African (AFR) AF: 0.950 AC: 29926 AN: 31500

American (AMR) AF: 0.823 AC: 33760 AN: 41006

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 15073 AN: 25238

East Asian (EAS) AF: 0.999 AC: 39314 AN: 39342

South Asian (SAS) AF: 0.874 AC: 71733 AN: 82072

European-Finnish (FIN) AF: 0.749 AC: 39816 AN: 53146

Middle Eastern (MID) AF: 0.667 AC: 3681 AN: 5522

European-Non Finnish (NFE) AF: 0.650 AC: 686705 AN: 1057102

Other (OTH) AF: 0.709 AC: 41052 AN: 57864

GnomAD4 genome AF: 0.763 AC: 116185 AN: 152212 Hom.: 45827 Cov.: 33 AF XY: 0.771 AC XY: 57360 AN XY: 74404

African (AFR) AF: 0.940 AC: 39090 AN: 41568

American (AMR) AF: 0.760 AC: 11610 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2111 AN: 3470

East Asian (EAS) AF: 0.997 AC: 5174 AN: 5188

South Asian (SAS) AF: 0.885 AC: 4276 AN: 4832

European-Finnish (FIN) AF: 0.751 AC: 7946 AN: 10576

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43764 AN: 67972

Other (OTH) AF: 0.731 AC: 1546 AN: 2116

Alfa AF: 0.671 Hom.: 45020

Bravo AF: 0.771

Asia WGS AF: 0.944 AC: 3280 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.32
PhyloP100		-0.43
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs7967622; hg19: chr12-54677980;