chr3-23916438-A-G

Variant names:

• chr3-23916438-A-G
• rs2360610
• NM_020345.4:c.-140+346T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020345.4(NKIRAS1):​c.-140+346T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 152,174 control chromosomes in the GnomAD database, including 10,741 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (10739 hom., cov: 33)
  • Exomes 𝑓: 0.36 (2 hom.)
• Consequence: NKIRAS1 NM_020345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.881
• Publications: 11 publications found

Genes affected

NKIRAS1 (HGNC:17899): (NFKB inhibitor interacting Ras like 1) Predicted to enable GTPase activating protein binding activity. Predicted to be involved in I-kappaB kinase/NF-kappaB signaling. Predicted to act upstream of or within several processes, including Ral protein signal transduction; lung alveolus development; and surfactant homeostasis. Located in cytosol and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

RPL15 (HGNC:10306): (ribosomal protein L15) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a member of the L15E family of ribosomal proteins and a component of the 60S subunit. This gene shares sequence similarity with the yeast ribosomal protein YL10 gene. Elevated expression of this gene has been observed in esophageal tumors and gastric cancer tissues, and deletion of this gene has been observed in a Diamond-Blackfan anemia (DBA) patient. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Mar 2017]

RPL15 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020345.4. 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
	NKIRAS1	NM_020345.4	MANE Select	c.-140+346T>C		intron	N/A	NP_065078.1
	NKIRAS1	NM_001377351.1		c.-18+346T>C		intron	N/A	NP_001364280.1
	NKIRAS1	NM_001377352.1		c.-140+427T>C		intron	N/A	NP_001364281.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKIRAS1	ENST00000425478.7	TSL:1 MANE Select	c.-140+346T>C		intron	N/A	ENSP00000400385.2
	NKIRAS1	ENST00000443659.6	TSL:5	c.-501T>C		5_prime_UTR	Exon 1 of 4	ENSP00000393785.2
	NKIRAS1	ENST00000388759.7	TSL:3	c.-136+346T>C		intron	N/A	ENSP00000373411.3

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55568 AN: 152020 Hom.: 10722 Cov.: 33

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.391

GnomAD4 exome AF: 0.361 AC: 13 AN: 36 Hom.: 2 Cov.: 0 AF XY: 0.367 AC XY: 11 AN XY: 30

African (AFR) AF: 0.250 AC: 2 AN: 8

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.423 AC: 11 AN: 26

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.366 AC: 55610 AN: 152138 Hom.: 10739 Cov.: 33 AF XY: 0.364 AC XY: 27051 AN XY: 74374

African (AFR) AF: 0.229 AC: 9502 AN: 41518

American (AMR) AF: 0.394 AC: 6032 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1360 AN: 3472

East Asian (EAS) AF: 0.427 AC: 2202 AN: 5160

South Asian (SAS) AF: 0.382 AC: 1841 AN: 4824

European-Finnish (FIN) AF: 0.342 AC: 3612 AN: 10564

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29840 AN: 67982

Other (OTH) AF: 0.394 AC: 832 AN: 2114

Alfa AF: 0.407 Hom.: 29391

Bravo AF: 0.368

Asia WGS AF: 0.399 AC: 1390 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.8
DANN	Benign	0.66
PhyloP100		0.88
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2360610; hg19: chr3-23957929;