rs139561508

Variant names:

• chr1-244863801-C-G
• rs139561508
• NM_031844.3:c.507G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-244863801-C-G
• chr1-244863801-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_031844.3(HNRNPU):​c.507G>C​(p.Gln169His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q169L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNRNPU NM_031844.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.854
• Publications: 1 publications found

Genes affected

HNRNPU (HGNC:5048): (heterogeneous nuclear ribonucleoprotein U) This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]

HNRNPU Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 54

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ENSG00000273175 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15165326).
• BP6: Variant 1-244863801-C-G is Benign according to our data. Variant chr1-244863801-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 836208.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031844.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPU	NM_031844.3	MANE Select	c.507G>C	p.Gln169His	missense	Exon 1 of 14	NP_114032.2
	HNRNPU	NM_004501.3		c.507G>C	p.Gln169His	missense	Exon 1 of 14	NP_004492.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPU	ENST00000640218.2	TSL:1 MANE Select	c.507G>C	p.Gln169His	missense	Exon 1 of 14	ENSP00000491215.1
	HNRNPU	ENST00000444376.7	TSL:1	c.507G>C	p.Gln169His	missense	Exon 1 of 14	ENSP00000393151.2
	HNRNPU	ENST00000283179.14	TSL:5	c.507G>C	p.Gln169His	missense	Exon 1 of 12	ENSP00000283179.10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000423 AC: 1 AN: 236224 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457262 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 724734

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110790

Other (OTH) AF: 0.00 AC: 0 AN: 60170

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 54 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.85
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.025
Sift	Benign	0.11	T
Sift4G	Uncertain	0.030	D
Polyphen		0.12	B
Vest4		0.15
MutPred		0.23		Loss of helix (P = 0.0558)
MVP		0.50
MPC		0.59
ClinPred		0.086	T
GERP RS		2.8
PromoterAI		-0.065	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3
Varity_R		0.14
gMVP		0.25
Mutation Taster		=87/13	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: rs139561508; hg19: chr1-245027103;