18-62187732-C-T

Position:

• chr18-62187732-C-T

Variant summary

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

The NM_001346235.2(RELCH):​c.-2147C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000686 in 1,456,812 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: RELCH NM_001346235.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.59

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1809757).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELCH	NM_001346231.2	c.227C>T	p.Ser76Leu	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.227C>T	p.Ser76Leu	missense_variant	1/29		NM_001346231.2	ENSP00000494314.1
RELCH	ENST00000398130.6	c.227C>T	p.Ser76Leu	missense_variant	1/29	1		ENSP00000381198.2
RELCH	ENST00000256858.10	c.227C>T	p.Ser76Leu	missense_variant	1/30	5		ENSP00000256858.5
RELCH	ENST00000587725.5	n.227C>T		non_coding_transcript_exon_variant	1/22	2		ENSP00000468816.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1456812 Hom.: 0 Cov.: 31 AF XY: 0.00000829 AC XY: 6 AN XY: 724022

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: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.0000167

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

Jan 22, 2024

The c.227C>T (p.S76L) alteration is located in exon 1 (coding exon 1) of the KIAA1468 gene. This alteration results from a C to T substitution at nucleotide position 227, causing the serine (S) at amino acid position 76 to be replaced by a leucine (L). 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	0.088
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	.;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.0	.;N;N
REVEL	Benign	0.026
Sift	Benign	0.037	.;D;T
Sift4G	Benign	0.32	.;T;T
Polyphen		0.023, 0.0020	.;B;B
Vest4		0.19, 0.18
MutPred		0.32		Loss of glycosylation at S76 (P = 0.0023);Loss of glycosylation at S76 (P = 0.0023);Loss of glycosylation at S76 (P = 0.0023);
MVP		0.082
MPC		0.65
ClinPred		0.67	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.31

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: rs1169252134; hg19: chr18-59854965;