2-3575643-A-C

Position:

• chr2-3575643-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001011.4(RPS7):​c.34A>C​(p.Asn12His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N12S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS7 NM_001011.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.82

Genes affected

RPS7 (HGNC:10440): (ribosomal protein S7) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S7E family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30302212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS7	NM_001011.4	c.34A>C	p.Asn12His	missense_variant	2/7	ENST00000645674.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS7	ENST00000645674.2	c.34A>C	p.Asn12His	missense_variant	2/7		NM_001011.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2019

This sequence change replaces asparagine with histidine at codon 12 of the RPS7 protein (p.Asn12His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RPS7-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.00012	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;T;T;.;T;T;.;T
Eigen	Benign	-0.015
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	.;.;.;D;.;.;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L;L;L;.;L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;.;.;.;.;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.066	T;.;.;.;.;T;T;T
Sift4G	Benign	0.10	T;.;.;.;.;T;T;T
Polyphen		0.0060	B;B;B;.;B;B;B;B
Vest4		0.66
MutPred		0.34		Gain of glycosylation at K15 (P = 0.1144);Gain of glycosylation at K15 (P = 0.1144);Gain of glycosylation at K15 (P = 0.1144);Gain of glycosylation at K15 (P = 0.1144);Gain of glycosylation at K15 (P = 0.1144);Gain of glycosylation at K15 (P = 0.1144);Gain of glycosylation at K15 (P = 0.1144);Gain of glycosylation at K15 (P = 0.1144);
MVP		0.43
MPC		2.1
ClinPred		0.96	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.46

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: rs1661257045; hg19: chr2-3623233;