1-241633888-C-T

Variant names:

• chr1-241633888-C-T
• rs763138761
• NM_001381853.1:c.1879G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001381853.1(CHML):​c.1879G>A​(p.Ala627Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. A627S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHML NM_001381853.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0290
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027280778).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001381853.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHML	NM_001381853.1	MANE Select	c.1879G>A	p.Ala627Thr	missense	Exon 2 of 2	NP_001368782.1	P26374
	OPN3	NM_014322.3	MANE Select	c.373+5994G>A		intron	N/A	NP_055137.2	Q9H1Y3-1
	CHML	NM_001381854.1		c.1879G>A	p.Ala627Thr	missense	Exon 2 of 2	NP_001368783.1	P26374

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHML	ENST00000366553.3	TSL:2 MANE Select	c.1879G>A	p.Ala627Thr	missense	Exon 2 of 2	ENSP00000355511.1	P26374
	OPN3	ENST00000366554.3	TSL:1 MANE Select	c.373+5994G>A		intron	N/A	ENSP00000355512.2	Q9H1Y3-1
	OPN3	ENST00000469376.5	TSL:1	n.373+5994G>A		intron	N/A	ENSP00000490012.1	Q6P5W7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461596 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111798

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.059
DANN	Benign	0.40
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.029
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.26
Sift	Benign	0.37	T
Sift4G	Benign	0.44	T
Polyphen		0.20	B
Vest4		0.021
MutPred		0.091		Gain of glycosylation at A627 (P = 0.0293)
MVP		0.45
MPC		0.034
ClinPred		0.066	T
GERP RS		-6.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.24
Mutation Taster		=97/3	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

dbSNP: rs763138761; hg19: chr1-241797190; COSMIC: COSV59367611; COSMIC: COSV59367611;