X-70290531-A-G

Position:

• chrX-70290531-A-G

Variant summary

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

The NM_012310.5(KIF4A):​c.73A>G​(p.Ser25Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,104 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: KIF4A NM_012310.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

Genes affected

KIF4A (HGNC:13339): (kinesin family member 4A) This gene encodes a member of the kinesin 4 subfamily of kinesin related proteins. The encoded protein is an ATP dependent microtubule-based motor protein that is involved in the intracellular transport of membranous organelles. This protein also associates with condensed chromosome arms and may be involved in maintaining chromosome integrity during mitosis. This protein may also be involved in the organization of the central spindle prior to cytokinesis. A pseudogene of this gene is found on chromosome X.[provided by RefSeq, Mar 2010]

KIF4A (HGNC:):

PDZD11 (HGNC:28034): (PDZ domain containing 11) Enables protein C-terminus binding activity. Involved in pore complex assembly. Located in basolateral plasma membrane and cytosol. Part of pore complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.102517605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF4A	NM_012310.5	c.73A>G	p.Ser25Gly	missense_variant	2/31	ENST00000374403.4	NP_036442.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF4A	ENST00000374403.4	c.73A>G	p.Ser25Gly	missense_variant	2/31	1	NM_012310.5	ENSP00000363524.3
KIF4A	ENST00000485406.1	n.318A>G		non_coding_transcript_exon_variant	2/4	4
PDZD11	ENST00000486461.2	c.-141T>C		upstream_gene_variant		3		ENSP00000512019.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363458

Gnomad4 AFR exome AF: 0.0000379

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.92	L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.15
Sift	Benign	0.34	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.088
MutPred		0.46		Gain of catalytic residue at P21 (P = 0.0665);
MVP		0.75
MPC		1.2
ClinPred		0.21	T
GERP RS		3.8
Varity_R		0.17
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-69510381;