19-8445104-C-T

Variant names:

• chr19-8445104-C-T
• rs760282480
• NM_005968.5:c.106C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005968.5(HNRNPM):​c.106C>T​(p.Pro36Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000567 in 1,410,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P36A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HNRNPM NM_005968.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.282
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06835115).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.106C>T	p.Pro36Ser	missense	Exon 1 of 16	NP_005959.2
	HNRNPM	NM_031203.4		c.106C>T	p.Pro36Ser	missense	Exon 1 of 17	NP_112480.2	P52272-2
	HNRNPM	NM_001297418.2		c.-202C>T		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.106C>T	p.Pro36Ser	missense	Exon 1 of 16	ENSP00000325376.2	P52272-1
	HNRNPM	ENST00000348943.7	TSL:1	c.106C>T	p.Pro36Ser	missense	Exon 1 of 17	ENSP00000325732.2	P52272-2
	HNRNPM	ENST00000940928.1		c.106C>T	p.Pro36Ser	missense	Exon 1 of 15	ENSP00000610987.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151894 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

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 AF: 0.00000477 AC: 6 AN: 1258446 Hom.: 0 Cov.: 30 AF XY: 0.00000488 AC XY: 3 AN XY: 614884

African (AFR) AF: 0.000161 AC: 4 AN: 24782

American (AMR) AF: 0.00 AC: 0 AN: 10874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19520

East Asian (EAS) AF: 0.00 AC: 0 AN: 28662

South Asian (SAS) AF: 0.00 AC: 0 AN: 58924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5086

European-Non Finnish (NFE) AF: 9.87e-7 AC: 1 AN: 1012984

Other (OTH) AF: 0.0000196 AC: 1 AN: 51120

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151894 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74214

African (AFR) AF: 0.0000484 AC: 2 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

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	Benign	0.070
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.28
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.051
Sift	Benign	0.56	T
Sift4G	Benign	0.75	T
Polyphen		0.098	B
Vest4		0.24
MutPred		0.17		Gain of phosphorylation at P36 (P = 0.0191)
MVP		0.47
MPC		0.58
ClinPred		0.12	T
GERP RS		3.9
PromoterAI		-0.065	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.080
gMVP		0.37
Mutation Taster		=91/9	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: rs760282480; hg19: chr19-8509988;