1-42399464-C-A

Variant names:

• chr1-42399464-C-A
• NM_173642.4:c.224C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173642.4(RIMKLA):​c.224C>A​(p.Pro75His) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIMKLA NM_173642.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97

Genes affected

RIMKLA (HGNC:28725): (ribosomal modification protein rimK like family member A) Predicted to enable N-acetyl-L-aspartate-L-glutamate ligase activity. Predicted to be involved in glutamine family amino acid metabolic process. Predicted to be located in cytosol. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41062203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIMKLA	NM_173642.4	c.224C>A	p.Pro75His	missense_variant	Exon 2 of 5	ENST00000431473.4	NP_775913.2
RIMKLA	XM_006710585.4	c.224C>A	p.Pro75His	missense_variant	Exon 2 of 5		XP_006710648.1
RIMKLA	XM_047418484.1	c.-149C>A		5_prime_UTR_variant	Exon 3 of 6		XP_047274440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIMKLA	ENST00000431473.4	c.224C>A	p.Pro75His	missense_variant	Exon 2 of 5	1	NM_173642.4	ENSP00000414330.2
RIMKLA	ENST00000410070.6	c.-149C>A		5_prime_UTR_variant	Exon 3 of 5	3		ENSP00000387064.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.224C>A (p.P75H) alteration is located in exon 2 (coding exon 2) of the RIMKLA gene. This alteration results from a C to A substitution at nucleotide position 224, causing the proline (P) at amino acid position 75 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.0
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.26
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.013	D
Polyphen		0.85	P
Vest4		0.48
MutPred		0.56		Gain of sheet (P = 0.039);
MVP		0.055
MPC		1.1
ClinPred		0.92	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.15
gMVP		0.53
Mutation Taster		=71/29	polymorphism

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

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Other links and lift over

hg19: chr1-42865135;