10-43386645-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001098204.2(HNRNPF):c.1240T>G(p.Tyr414Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPF NM_001098204.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.57

Genes affected

HNRNPF (HGNC:5039): (heterogeneous nuclear ribonucleoprotein F) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins that complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and regulate alternative splicing, polyadenylation, 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 has three repeats of quasi-RRM domains that bind to RNAs which have guanosine-rich sequences. This protein is very similar to the family member hnRPH. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HNRNPF
• BP4: Computational evidence support a benign effect (MetaRNN=0.21576989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPF	NM_001098204.2	c.1240T>G	p.Tyr414Asp	missense_variant	4/4	ENST00000682386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPF	ENST00000682386.1	c.1240T>G	p.Tyr414Asp	missense_variant	4/4		NM_001098204.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

The c.1240T>G (p.Y414D) alteration is located in exon 3 (coding exon 1) of the HNRNPF gene. This alteration results from a T to G substitution at nucleotide position 1240, causing the tyrosine (Y) at amino acid position 414 to be replaced by an aspartic acid (D). 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
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;D;D;D;D
Eigen	Benign	-0.011
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.58	T;.;.;.;.
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.041	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.041	B;B;B;B;B
Vest4		0.31
MutPred		0.27		Loss of phosphorylation at Y414 (P = 0.0205);Loss of phosphorylation at Y414 (P = 0.0205);Loss of phosphorylation at Y414 (P = 0.0205);Loss of phosphorylation at Y414 (P = 0.0205);Loss of phosphorylation at Y414 (P = 0.0205);
MVP		0.66
MPC		1.5
ClinPred		0.85	D
GERP RS		4.4
Varity_R		0.22
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-43882093;