chr21-14964763-A-C
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2
The NM_003489.4(NRIP1):āc.3430T>Gā(p.Tyr1144Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,582,388 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ).
Frequency
Consequence
NM_003489.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NRIP1 | ENST00000318948.7 | c.3430T>G | p.Tyr1144Asp | missense_variant | Exon 4 of 4 | 2 | NM_003489.4 | ENSP00000327213.4 | ||
NRIP1 | ENST00000400199.5 | c.3430T>G | p.Tyr1144Asp | missense_variant | Exon 3 of 3 | 3 | ENSP00000383060.1 | |||
NRIP1 | ENST00000400202.5 | c.3430T>G | p.Tyr1144Asp | missense_variant | Exon 3 of 3 | 5 | ENSP00000383063.1 | |||
ENSG00000235609 | ENST00000432230.6 | n.87+49581T>G | intron_variant | Intron 1 of 3 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000861 AC: 131AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000875 AC: 193AN: 220458Hom.: 0 AF XY: 0.000805 AC XY: 96AN XY: 119328
GnomAD4 exome AF: 0.00120 AC: 1709AN: 1430106Hom.: 2 Cov.: 32 AF XY: 0.00117 AC XY: 834AN XY: 710750
GnomAD4 genome AF: 0.000860 AC: 131AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54AN XY: 74472
ClinVar
Submissions by phenotype
not provided Benign:2
The NRIP1 p.Y1144D variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs61733441) and in control databases in 210 of 251860 chromosomes at a frequency of 0.0008338, and was observed at the highest frequency in the European (non-Finnish) population in 150 of 119394 chromosomes (freq: 0.001256) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant congenital anomalies of kidney and urinary tract 3 condition associated with NRIP1 variants. The p.Y1144 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
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NRIP1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at