rs1004620613

Variant names:

• chr2-177219247-G-A
• rs1004620613
• NM_194247.4:c.1085G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_194247.4(HNRNPA3):​c.1085G>A​(p.Gly362Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: HNRNPA3 NM_194247.4 missense, splice_region
• Scores: Splicing: ADA: 0.04353
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

HNRNPA3 (HGNC:24941): (heterogeneous nuclear ribonucleoprotein A3) Enables RNA binding activity. Predicted to be involved in mRNA splicing, via spliceosome. Located in nucleoplasm. Part of catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

NFE2L2 (HGNC:7782): (NFE2 like bZIP transcription factor 2) This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]

NFE2L2 Gene-Disease associations (from GenCC):

• immunodeficiency, developmental delay, and hypohomocysteinemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194247.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA3	NM_194247.4	MANE Select	c.1085G>A	p.Gly362Asp	missense splice_region	Exon 10 of 11	NP_919223.1	P51991-1
	HNRNPA3	NM_001330249.2		c.1085G>A	p.Gly362Asp	missense splice_region	Exon 10 of 11	NP_001317178.1	P51991-1
	HNRNPA3	NM_001330247.2		c.1019G>A	p.Gly340Asp	missense splice_region	Exon 10 of 11	NP_001317176.1	P51991-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPA3	ENST00000392524.7	TSL:5 MANE Select	c.1085G>A	p.Gly362Asp	missense splice_region	Exon 10 of 11	ENSP00000376309.2	P51991-1
	HNRNPA3	ENST00000435711.5	TSL:1	c.1085G>A	p.Gly362Asp	missense splice_region	Exon 10 of 10	ENSP00000416340.1	P51991-1
	HNRNPA3	ENST00000679328.1		c.1139G>A	p.Gly380Asp	missense splice_region	Exon 10 of 11	ENSP00000503903.1	A0A7I2V4G0

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.0000724 AC: 3 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Benign	0.89
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.060
Eigen_PC	Benign	0.0074
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.45
Sift	Benign	0.039	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.0020	B
Vest4		0.48
MutPred		0.42		Loss of sheet (P = 0.0457)
MVP		0.86
MPC		1.2
ClinPred		0.96	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
gMVP		0.99
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.044
dbscSNV1_RF	Benign	0.22
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: rs1004620613; hg19: chr2-178083975;