18-62187546-G-C

Position:

• chr18-62187546-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001346231.2(RELCH):​c.41G>C​(p.Gly14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000734 in 1,363,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RELCH NM_001346231.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

Genes affected

RELCH (HGNC:29289): (RAB11 binding and LisH domain, coiled-coil and HEAT repeat containing) Involved in intracellular cholesterol transport. Located in recycling endosome and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

RELCH (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28600052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELCH	NM_001346231.2	c.41G>C	p.Gly14Ala	missense_variant	1/29	ENST00000644646.2	NP_001333160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELCH	ENST00000644646.2	c.41G>C	p.Gly14Ala	missense_variant	1/29		NM_001346231.2	ENSP00000494314.1
RELCH	ENST00000398130.6	c.41G>C	p.Gly14Ala	missense_variant	1/29	1		ENSP00000381198.2
RELCH	ENST00000256858.10	c.41G>C	p.Gly14Ala	missense_variant	1/30	5		ENSP00000256858.5
RELCH	ENST00000587725.5	n.41G>C		non_coding_transcript_exon_variant	1/22	2		ENSP00000468816.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1363120 Hom.: 0 Cov.: 30 AF XY: 0.00000150 AC XY: 1 AN XY: 667018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000344

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.: 33

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

Dec 10, 2024

The c.41G>C (p.G14A) alteration is located in exon 1 (coding exon 1) of the KIAA1468 gene. This alteration results from a G to C substitution at nucleotide position 41, causing the glycine (G) at amino acid position 14 to be replaced by an alanine (A). 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	0.092
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.83	T
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	.;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.023	.;D;D
Sift4G	Benign	0.38	.;T;T
Polyphen		1.0, 0.99	.;D;D
Vest4		0.23, 0.24
MutPred		0.11		Gain of catalytic residue at G14 (P = 0.1731);Gain of catalytic residue at G14 (P = 0.1731);Gain of catalytic residue at G14 (P = 0.1731);
MVP		0.27
MPC		1.8
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.20
gMVP		0.40

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: chr18-59854779;