Genetic Variant CHML:p.Glu535Gly (chr1-241634163-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001381853.1(CHML):c.1604A>G(p.Glu535Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 152,198 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: 𝑓 0.000033 ( 0 hom., cov: 32)

Consequence

CHML
NM_001381853.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.64

Variant links:

Genes affected

CHML (HGNC:1941): (CHM like Rab escort protein) The product of the CHML gene supports geranylgeranylation of most Rab proteins and may substitute for REP-1 in tissues other than retina. CHML is localized close to the gene for Usher syndrome type II. [provided by RefSeq, Jul 2008]

CHML links:

OPN3 (HGNC:14007): (opsin 3) Opsins are members of the guanine nucleotide-binding protein (G protein)-coupled receptor superfamily. In addition to the visual opsins, mammals possess several photoreceptive non-visual opsins that are expressed in extraocular tissues. This gene, opsin 3, is strongly expressed in brain and testis and weakly expressed in liver, placenta, heart, lung, skeletal muscle, kidney, and pancreas. The gene may also be expressed in the retina. The protein has the canonical features of a photoreceptive opsin protein. [provided by RefSeq, Jul 2008]

OPN3 links:

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ACMG classification

Classification made for transcript

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=0.4175074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHML	NM_001381853.1 link	c.1604A>G	p.Glu535Gly	missense_variant	Exon 2 of 2	ENST00000366553.3	NP_001368782.1
OPN3	NM_014322.3 link	c.373+5719A>G		intron_variant	Intron 1 of 3	ENST00000366554.3	NP_055137.2	Q9H1Y3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHML	ENST00000366553.3 link	c.1604A>G	p.Glu535Gly	missense_variant	Exon 2 of 2	2	NM_001381853.1	ENSP00000355511.1		P26374
OPN3	ENST00000366554.3 link	c.373+5719A>G		intron_variant	Intron 1 of 3	1	NM_014322.3	ENSP00000355512.2		Q9H1Y3-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1604A>G (p.E535G) alteration is located in exon 1 (coding exon 1) of the CHML gene. This alteration results from a A to G substitution at nucleotide position 1604, causing the glutamic acid (E) at amino acid position 535 to be replaced by a glycine (G). 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

0.084

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

0.0091

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.42

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.2

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.013

Polyphen

0.99

Vest4

0.18

MVP

0.92

MPC

0.17

ClinPred

0.88

GERP RS

3.4

Varity_R

0.11

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over