chr19-17420570-G-C

Position:

• chr19-17420570-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138401.4(MVB12A):​c.222G>C​(p.Gln74His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MVB12A NM_138401.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

Genes affected

MVB12A (HGNC:25153): (multivesicular body subunit 12A) Enables lipid binding activity and ubiquitin binding activity. Involved in regulation of epidermal growth factor receptor signaling pathway; viral budding; and virus maturation. Located in several cellular components, including Golgi apparatus; centrosome; and nucleoplasm. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

MVB12A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MVB12A	NM_138401.4	c.222G>C	p.Gln74His	missense_variant	3/9	ENST00000317040.12	NP_612410.1
MVB12A	NM_001304547.2	c.-55G>C		5_prime_UTR_variant	4/10		NP_001291476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MVB12A	ENST00000317040.12	c.222G>C	p.Gln74His	missense_variant	3/9	1	NM_138401.4	ENSP00000324810.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.222G>C (p.Q74H) alteration is located in exon 3 (coding exon 3) of the MVB12A gene. This alteration results from a G to C substitution at nucleotide position 222, causing the glutamine (Q) at amino acid position 74 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	Benign	0.26
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.76	.;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.3	M;.;.;M
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N;D;D;N
REVEL	Benign	0.25
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		0.99	D;.;.;D
Vest4		0.55
MutPred		0.61		Loss of ubiquitination at K79 (P = 0.0935);Loss of ubiquitination at K79 (P = 0.0935);Loss of ubiquitination at K79 (P = 0.0935);Loss of ubiquitination at K79 (P = 0.0935);
MVP		0.72
MPC		0.63
ClinPred		0.97	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.58

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: rs2074831862; hg19: chr19-17531379;