17-30116845-T-C

Variant names:

• chr17-30116845-T-C
• rs773958282
• NM_032141.4:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_032141.4(NSRP1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,575,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: NSRP1 NM_032141.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52
• Publications: 1 publications found

Genes affected

NSRP1 (HGNC:25305): (nuclear speckle splicing regulatory protein 1) Enables mRNA binding activity. Involved in developmental process and regulation of alternative mRNA splicing, via spliceosome. Located in nuclear speck. Part of ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000265394 (HGNC:):

MIR423 (HGNC:31880): (microRNA 423) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR3184 (HGNC:38182): (microRNA 3184) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 55 codons. Genomic position: 30172590. Lost 0.097 part of the original CDS.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032141.4. 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
	NSRP1	NM_032141.4	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	NP_115517.1	Q9H0G5
	NSRP1	NM_001261467.2		c.-67T>C		5_prime_UTR	Exon 1 of 6	NP_001248396.1	A0A024QZ33
	MIR423	NR_029945.1		n.-234T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSRP1	ENST00000247026.10	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENSP00000247026.5	Q9H0G5
	NSRP1	ENST00000612959.4	TSL:1	c.-67T>C		5_prime_UTR	Exon 1 of 6	ENSP00000477862.1	A0A024QZ33
	NSRP1	ENST00000394826.8	TSL:1	n.2T>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000378303.4	H7BYM1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000121 AC: 23 AN: 190150 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000431

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000697

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000985

Gnomad OTH exome AF: 0.000402

GnomAD4 exome AF: 0.000112 AC: 160 AN: 1423556 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 76 AN XY: 704266

African (AFR) AF: 0.000153 AC: 5 AN: 32742

American (AMR) AF: 0.000362 AC: 14 AN: 38648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25426

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37920

South Asian (SAS) AF: 0.00 AC: 0 AN: 81014

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.000125 AC: 136 AN: 1092234

Other (OTH) AF: 0.0000508 AC: 3 AN: 59006

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74298

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.000786 AC: 12 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.0000418 AC: 5

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
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.69	T
PhyloP100		3.5
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.97
MVP		0.62
ClinPred		0.85	D
GERP RS		5.3
PromoterAI		-0.80	Under-expression
Varity_R		0.85
gMVP		0.48
Mutation Taster		=29/171	disease causing

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: rs773958282; hg19: chr17-28443863;