17-30116845-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

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

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

Verdict is Uncertain_significance. Variant got 4 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.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSRP1	NM_032141.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENST00000247026.10	NP_115517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSRP1	ENST00000247026.10	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	1	NM_032141.4	ENSP00000247026.5

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

GnomAD3 exomes AF: 0.000121 AC: 23 AN: 190150 Hom.: 0 AF XY: 0.000118 AC XY: 12 AN XY: 101360

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.000362

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000264

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.0000508

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.0000418 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NSRP1 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 190150 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NSRP1 causing Neurodevelopmental Disorder With Spasticity, Seizures, And Brain Abnormalities, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2T>C in individuals affected with Neurodevelopmental Disorder With Spasticity, Seizures, And Brain Abnormalities and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

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;D;.
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.69	T
PROVEAN	Uncertain	-2.8	.;D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.98	.;D;.
Vest4		0.97
MVP		0.62
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.85
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

LitVar

Other links and lift over

dbSNP: rs773958282; hg19: chr17-28443863;