X-73447569-G-T

Position:

• chrX-73447569-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005193.2(CDX4):​c.316G>T​(p.Ala106Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,097,764 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 0 hem.)
• Consequence: CDX4 NM_005193.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

Genes affected

CDX4 (HGNC:1808): (caudal type homeobox 4) This gene encodes a member of a small subfamily of homeobox containing transcription factors. The encoded protein may regulate homeobox gene expression during anteroposterior patterning and hematopoiesis. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07980806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDX4	NM_005193.2	c.316G>T	p.Ala106Ser	missense_variant	1/3	ENST00000373514.3	NP_005184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDX4	ENST00000373514.3	c.316G>T	p.Ala106Ser	missense_variant	1/3	1	NM_005193.2	ENSP00000362613.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097764 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363146

Gnomad4 AFR exome AF: 0.0000758

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: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

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

May 14, 2024

The c.316G>T (p.A106S) alteration is located in exon 1 (coding exon 1) of the CDX4 gene. This alteration results from a G to T substitution at nucleotide position 316, causing the alanine (A) at amino acid position 106 to be replaced by a serine (S). 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	0.073
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.71
DANN	Benign	0.81
DEOGEN2	Benign	0.077	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.052
Sift	Benign	0.39	T
Sift4G	Benign	0.54	T
Polyphen		0.0070	B
Vest4		0.090
MutPred		0.49		Gain of glycosylation at A106 (P = 0.0323);
MVP		0.57
MPC		0.10
ClinPred		0.053	T
GERP RS		-0.74
Varity_R		0.059
gMVP		0.39

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: rs750486027; hg19: chrX-72667405;