5-178210248-G-A

Variant names:

• chr5-178210248-G-A
• rs1432021904
• NM_031266.3:c.904G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_031266.3(HNRNPAB):​c.904G>A​(p.Gly302Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HNRNPAB NM_031266.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

Genes affected

HNRNPAB (HGNC:5034): (heterogeneous nuclear ribonucleoprotein A/B) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are produced by RNA polymerase II and are components of the heterogeneous nuclear RNA (hnRNA) complexes. They are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene, which binds to one of the components of the multiprotein editosome complex, has two repeats of quasi-RRM (RNA recognition motif) domains that bind to RNAs. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

PHYKPL (HGNC:28249): (5-phosphohydroxy-L-lysine phospho-lyase) This is a nuclear gene encoding a mitochondrial enzyme that catalyzes the conversion of 5-phosphonooxy-L-lysine to ammonia, inorganic phosphate, and 2-aminoadipate semialdehyde. Mutations in this gene may cause phosphohydroxylysinuria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28750396).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPAB	NM_031266.3	c.904G>A	p.Gly302Ser	missense_variant	Exon 7 of 8	ENST00000358344.8	NP_112556.2
PHYKPL	NM_153373.4	c.*32-1333C>T		intron_variant	Intron 12 of 12	ENST00000308158.10	NP_699204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPAB	ENST00000358344.8	c.904G>A	p.Gly302Ser	missense_variant	Exon 7 of 8	1	NM_031266.3	ENSP00000351108.3
PHYKPL	ENST00000308158.10	c.*32-1333C>T		intron_variant	Intron 12 of 12	1	NM_153373.4	ENSP00000310978.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251252 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461640 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.904G>A (p.G302S) alteration is located in exon 7 (coding exon 6) of the HNRNPAB gene. This alteration results from a G to A substitution at nucleotide position 904, causing the glycine (G) at amino acid position 302 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.064	T;T;T
Polyphen		0.94	P;.;P
Vest4		0.30
MutPred		0.34		Gain of glycosylation at G302 (P = 0.0112);.;Gain of glycosylation at G302 (P = 0.0112);
MVP		0.76
MPC		0.47
ClinPred		0.42	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.51

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: rs1432021904; hg19: chr5-177637249; COSMIC: COSV57423174; COSMIC: COSV57423174;