1-155921567-A-T

Position:

• chr1-155921567-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000368321.8(KHDC4):​c.1074T>A​(p.Asn358Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N358S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: KHDC4 ENST00000368321.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

Genes affected

KHDC4 (HGNC:29145): (KH domain containing 4, pre-mRNA splicing factor) Enables RNA binding activity. Involved in mRNA splice site selection. Located in cytoplasm and nucleoplasm. Colocalizes with spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

KHDC4 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21772686).
• BS2: High AC in GnomAdExome4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHDC4	NM_014949.4	c.1074T>A	p.Asn358Lys	missense_variant	10/14	ENST00000368321.8	NP_055764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHDC4	ENST00000368321.8	c.1074T>A	p.Asn358Lys	missense_variant	10/14	1	NM_014949.4	ENSP00000357304.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727218

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: 0.0000351

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 10, 2022

The c.1074T>A (p.N358K) alteration is located in exon 10 (coding exon 10) of the KIAA0907 gene. This alteration results from a T to A substitution at nucleotide position 1074, causing the asparagine (N) at amino acid position 358 to be replaced by a lysine (K). 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	0.64
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.041
Sift	Benign	0.064	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.0040	B;B
Vest4		0.57
MutPred		0.26		Gain of methylation at N358 (P = 0.0023);Gain of methylation at N358 (P = 0.0023);
MVP		0.16
MPC		0.56
ClinPred		0.57	D
GERP RS		4.5
Varity_R		0.14
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-155891358;