chr3-49804973-G-A

Variant names:

• chr3-49804973-G-A
• rs2081422018
• NM_203370.2:c.844G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203370.2(INKA1):​c.844G>A​(p.Val282Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INKA1 NM_203370.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 0 publications found

Genes affected

INKA1 (HGNC:32480): (inka box actin regulator 1) Enables protein kinase binding activity and protein serine/threonine kinase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. Predicted to act upstream of or within neural tube development. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

UBA7 (HGNC:12471): (ubiquitin like modifier activating enzyme 7) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E1 ubiquitin-activating enzyme family. The encoded enzyme is a retinoid target that triggers promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARalpha) degradation and apoptosis in acute promyelocytic leukemia, where it is involved in the conjugation of the ubiquitin-like interferon-stimulated gene 15 protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123578936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INKA1	NM_203370.2	c.844G>A	p.Val282Ile	missense_variant	Exon 2 of 2	ENST00000333323.6	NP_976248.2
INKA1	NM_001366281.1	c.763G>A	p.Val255Ile	missense_variant	Exon 2 of 2		NP_001353210.1
UBA7	NM_003335.3	c.*335C>T		downstream_gene_variant		ENST00000333486.4	NP_003326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INKA1	ENST00000333323.6	c.844G>A	p.Val282Ile	missense_variant	Exon 2 of 2	1	NM_203370.2	ENSP00000329735.5
UBA7	ENST00000333486.4	c.*335C>T		downstream_gene_variant		1	NM_003335.3	ENSP00000333266.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.850G>A (p.V284I) alteration is located in exon 2 (coding exon 2) of the FAM212A gene. This alteration results from a G to A substitution at nucleotide position 850, causing the valine (V) at amino acid position 284 to be replaced by an isoleucine (I). 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	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.11
Sift	Benign	0.59	T
Sift4G	Benign	0.91	T
Vest4		0.091
MVP		0.040
MPC		0.35
ClinPred		0.44	T
GERP RS		5.3
Mutation Taster		=83/17	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

Other links and lift over

dbSNP: rs2081422018; hg19: chr3-49842406;