Variant X-644478-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000451.4(SHOX):c.721T>G(p.Phe241Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000197 in 1,523,430 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F241L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., 0 hem., cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. 1 hem. )

Consequence

SHOX
NM_000451.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.55

Variant links:

Genes affected

SHOX (HGNC:10853): (SHOX homeobox) This gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Defects in this gene are associated with idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. This gene is highly conserved across species from mammals to fish to flies. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

SHOX links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Short stature homeobox protein (size 291) in uniprot entity SHOX_HUMAN there are 38 pathogenic changes around while only 6 benign (86%) in NM_000451.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22861835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4 linkuse as main transcript	c.721T>G	p.Phe241Val	missense_variant	5/5	ENST00000686671.1
SHOX	NM_006883.2 linkuse as main transcript	c.633+3391T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1 linkuse as main transcript	c.721T>G	p.Phe241Val	missense_variant	5/5		NM_000451.4	P1	O15266-1
SHOX	ENST00000381575.6 linkuse as main transcript	c.633+3391T>G		intron_variant		1			O15266-2
SHOX	ENST00000381578.6 linkuse as main transcript	c.721T>G	p.Phe241Val	missense_variant	6/6	5		P1	O15266-1
SHOX	ENST00000334060.8 linkuse as main transcript	c.633+3391T>G		intron_variant		5			O15266-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74264

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:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1371386

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

676932

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:

9.30e-7

Gnomad4 OTH exome

AF:

0.0000175

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Benign

0.034

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.54

Sift

Benign

0.50

Sift4G

Benign

0.48

Polyphen

0.90

Vest4

0.17

MutPred

0.23

Gain of phosphorylation at Y238 (P = 0.0896);

MVP

0.97

MPC

1.5

ClinPred

0.97

GERP RS

1.7

Varity_R

0.33

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over