12-54282620-G-A

Position:

• chr12-54282620-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_031157.4(HNRNPA1):​c.631G>A​(p.Gly211Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00034 in 1,613,916 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: HNRNPA1 NM_031157.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.96

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HNRNPA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.009534627).
• BP6: Variant 12-54282620-G-A is Benign according to our data. Variant chr12-54282620-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 706889.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-54282620-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000572 (87/152182) while in subpopulation AMR AF= 0.000785 (12/15282). AF 95% confidence interval is 0.000452. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPA1	NM_031157.4	c.631G>A	p.Gly211Ser	missense_variant	6/11	ENST00000340913.11
HNRNPA1	NM_002136.4	c.631G>A	p.Gly211Ser	missense_variant	6/10
HNRNPA1	NR_135167.2	n.713G>A		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPA1	ENST00000340913.11	c.631G>A	p.Gly211Ser	missense_variant	6/11	1	NM_031157.4
	ENST00000553061.1	n.545+5445G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00425

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000593 AC: 149 AN: 251168 Hom.: 0 AF XY: 0.000545 AC XY: 74 AN XY: 135826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00366

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000315 AC: 461 AN: 1461734 Hom.: 2 Cov.: 31 AF XY: 0.000303 AC XY: 220 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000982

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00311

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000726 AC XY: 54 AN XY: 74420

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00425

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000406 Hom.: 0

Bravo AF: 0.000276

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Benign	0.055
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.0095	T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.7	L;L;.;.;.
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N;N;N;N;D
REVEL	Uncertain	0.51
Sift	Benign	0.22	T;T;T;T;T
Sift4G	Benign	0.069	T;T;T;D;D
Polyphen		0.72	P;P;P;.;.
Vest4		0.40
MVP		0.82
MPC		0.49
ClinPred		0.055	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs182937540; hg19: chr12-54676404; COSMIC: COSV52936266; COSMIC: COSV52936266;