19-8445039-C-G

Variant names:

• chr19-8445039-C-G
• rs755869344
• NM_005968.5:c.41C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005968.5(HNRNPM):​c.41C>G​(p.Thr14Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T14K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: HNRNPM NM_005968.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• Publications: 0 publications found

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]

ENSG00000279827 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27311844).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005968.5. 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
	HNRNPM	NM_005968.5	MANE Select	c.41C>G	p.Thr14Arg	missense	Exon 1 of 16	NP_005959.2
	HNRNPM	NM_031203.4		c.41C>G	p.Thr14Arg	missense	Exon 1 of 17	NP_112480.2	P52272-2
	HNRNPM	NM_001297418.2		c.-267C>G		5_prime_UTR	Exon 1 of 14	NP_001284347.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPM	ENST00000325495.9	TSL:1 MANE Select	c.41C>G	p.Thr14Arg	missense	Exon 1 of 16	ENSP00000325376.2	P52272-1
	HNRNPM	ENST00000348943.7	TSL:1	c.41C>G	p.Thr14Arg	missense	Exon 1 of 17	ENSP00000325732.2	P52272-2
	HNRNPM	ENST00000940928.1		c.41C>G	p.Thr14Arg	missense	Exon 1 of 15	ENSP00000610987.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000235 AC: 3 AN: 1275472 Hom.: 0 Cov.: 30 AF XY: 0.00000320 AC XY: 2 AN XY: 624506

African (AFR) AF: 0.00 AC: 0 AN: 25384

American (AMR) AF: 0.00 AC: 0 AN: 13662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18254

East Asian (EAS) AF: 0.00 AC: 0 AN: 30050

South Asian (SAS) AF: 0.0000172 AC: 1 AN: 58074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5018

European-Non Finnish (NFE) AF: 9.74e-7 AC: 1 AN: 1026264

Other (OTH) AF: 0.0000192 AC: 1 AN: 52008

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.062	T
Polyphen		1.0	D
Vest4		0.49
MutPred		0.21		Loss of glycosylation at T14 (P = 0.035)
MVP		0.41
MPC		1.6
ClinPred		0.97	D
GERP RS		5.2
PromoterAI		-0.093	Neutral
Varity_R		0.52
gMVP		0.50
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs755869344; hg19: chr19-8509923;