Genetic Variant UNCX:p.Gly15Arg (chr7-1233060-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001080461.3(UNCX):c.43G>A(p.Gly15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000633 in 1,421,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

UNCX
NM_001080461.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

Variant links:

Genes affected

UNCX (HGNC:33194): (UNC homeobox) This gene encodes a homeobox transcription factor that is involved in somitogenesis and neurogenesis and is required for the maintenance and differentiation of specific elements of the axial skeleton. This gene also plays a role in controlling the development of connections of hypothalamic neurons to pituitary elements, allowing central neurons to reach the peripheral blood circulation and deliver hormones that control peripheral functions. The expression of this gene is associated with an increased frequency of acute myeloid leukemia. [provided by RefSeq, Jul 2017]

UNCX links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNCX	NM_001080461.3 link	c.43G>A	p.Gly15Arg	missense_variant	Exon 1 of 3	ENST00000316333.9	NP_001073930.1	A6NJT0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNCX	ENST00000316333.9 link	c.43G>A	p.Gly15Arg	missense_variant	Exon 1 of 3	1	NM_001080461.3	ENSP00000314480.8		A6NJT0

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000551

AC:

AN:

1269904

Hom.:

Cov.:

AF XY:

0.00000320

AC XY:

AN XY:

625606

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000688

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73842

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000111

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.43G>A (p.G15R) alteration is located in exon 1 (coding exon 1) of the UNCX gene. This alteration results from a G to A substitution at nucleotide position 43, causing the glycine (G) at amino acid position 15 to be replaced by an arginine (R). 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

0.87

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

0.11

Eigen_PC

Benign

0.035

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.66

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.53

MutPred

0.33

Gain of methylation at G15 (P = 0.0104);

MVP

0.59

ClinPred

0.98

GERP RS

2.6

Varity_R

0.78

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over