6-73363570-C-G

Variant names:

• chr6-73363570-C-G
• NM_001017361.3:c.364C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017361.3(KHDC3L):​c.364C>G​(p.Leu122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KHDC3L NM_001017361.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00200
• Publications: 0 publications found

Genes affected

KHDC3L (HGNC:33699): (KH domain containing 3 like, subcortical maternal complex member) The protein encoded by this gene belongs to the KHDC1 family, members of which contain an atypical KH domain that may not bind RNA like canonical KH domains. This gene is specifically expressed in the oocytes, and recent studies suggest that it may function as a regulator of genomic imprinting in the oocyte. Mutations in this gene are associated with recurrent biparental complete hydatidiform mole. [provided by RefSeq, Dec 2011]

KHDC3L Gene-Disease associations (from GenCC):

• hydatidiform mole, recurrent, 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• complete hydatidiform mole

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08618173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDC3L	NM_001017361.3	c.364C>G	p.Leu122Val	missense_variant	Exon 3 of 3	ENST00000370367.4	NP_001017361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KHDC3L	ENST00000370367.4	c.364C>G	p.Leu122Val	missense_variant	Exon 3 of 3	1	NM_001017361.3	ENSP00000359392.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.364C>G (p.L122V) alteration is located in exon 3 (coding exon 3) of the KHDC3L gene. This alteration results from a C to G substitution at nucleotide position 364, causing the leucine (L) at amino acid position 122 to be replaced by a valine (V). 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	0.064
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.3
DANN	Benign	0.55
DEOGEN2	Benign	0.0030	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.0020
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.060
Sift	Benign	0.17	T
Sift4G	Benign	0.37	T
Polyphen		0.60	P
Vest4		0.027
MutPred		0.24		Loss of helix (P = 0.0444);
MVP		0.25
MPC		0.59
ClinPred		0.37	T
GERP RS		0.095
Varity_R		0.070
gMVP		0.062
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

hg19: chr6-74073293;