chr19-8445039-C-A

Position:

• chr19-8445039-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005968.5(HNRNPM):​c.41C>A​(p.Thr14Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000235 in 1,275,472 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: 0.0000024 (0 hom.)
• Consequence: HNRNPM NM_005968.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

Genes affected

HNRNPM (HGNC:5046): (heterogeneous nuclear ribonucleoprotein M) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins 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 has three repeats of quasi-RRM domains that bind to RNAs. This protein also constitutes a monomer of the N-acetylglucosamine-specific receptor which is postulated to trigger selective recycling of immature GlcNAc-bearing thyroglobulin molecules. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2844808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPM	NM_005968.5	c.41C>A	p.Thr14Lys	missense_variant	1/16	ENST00000325495.9	NP_005959.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPM	ENST00000325495.9	c.41C>A	p.Thr14Lys	missense_variant	1/16	1	NM_005968.5	ENSP00000325376	P4
	ENST00000623944.1	n.559G>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000235 AC: 3 AN: 1275472 Hom.: 0 Cov.: 30 AF XY: 0.00000480 AC XY: 3 AN XY: 624506

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: 0.0000172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000195

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2023

The c.41C>A (p.T14K) alteration is located in exon 1 (coding exon 1) of the HNRNPM gene. This alteration results from a C to A substitution at nucleotide position 41, causing the threonine (T) at amino acid position 14 to be replaced by a lysine (K). 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	Benign	0.16
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T;T;T;T;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D;T;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L;.;.;.;.;.
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.70	N;N;.;.;.;.;.
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D;D;.;.;.;.;.
Sift4G	Benign	0.10	T;T;T;T;T;D;D
Polyphen		0.99	D;D;.;.;.;.;.
Vest4		0.48
MutPred		0.36		Gain of ubiquitination at T14 (P = 0.0037);Gain of ubiquitination at T14 (P = 0.0037);Gain of ubiquitination at T14 (P = 0.0037);Gain of ubiquitination at T14 (P = 0.0037);Gain of ubiquitination at T14 (P = 0.0037);Gain of ubiquitination at T14 (P = 0.0037);Gain of ubiquitination at T14 (P = 0.0037);
MVP		0.38
MPC		1.6
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.48

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: chr19-8509923;