chr1-171636449-A-T

Variant names:

• chr1-171636449-A-T
• rs137853276
• NM_000261.2:c.991T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The ENST00000037502.11(MYOC):​c.991T>A​(p.Ser331Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 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. S331L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC ENST00000037502.11 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: -0.525
• Publications: 4 publications found

Genes affected

MYOC (HGNC:7610): (myocilin) MYOC encodes the protein myocilin, which is believed to have a role in cytoskeletal function. MYOC is expressed in many occular tissues, including the trabecular meshwork, and was revealed to be the trabecular meshwork glucocorticoid-inducible response protein (TIGR). The trabecular meshwork is a specialized eye tissue essential in regulating intraocular pressure, and mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angle glaucoma. [provided by RefSeq, Jul 2008]

MYOCOS (HGNC:53429): (myocilin opposite strand)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000037502.11
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000037502.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOC	NM_000261.2	MANE Select	c.991T>A	p.Ser331Thr	missense	Exon 3 of 3	NP_000252.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOC	ENST00000037502.11	TSL:1 MANE Select	c.991T>A	p.Ser331Thr	missense	Exon 3 of 3	ENSP00000037502.5
	MYOC	ENST00000638471.1	TSL:5	n.*329T>A		non_coding_transcript_exon	Exon 4 of 4	ENSP00000491206.1
	MYOC	ENST00000638471.1	TSL:5	n.*329T>A		3_prime_UTR	Exon 4 of 4	ENSP00000491206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Open-angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	3.4
DANN	Benign	0.48
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.53
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.54
Sift	Benign	0.073	T
Sift4G	Benign	0.48	T
Polyphen		0.069	B
Vest4		0.38
MutPred		0.79		Loss of glycosylation at S331 (P = 0.1413)
MVP		0.49
MPC		0.17
ClinPred		0.13	T
GERP RS		-5.7
Varity_R		0.26
gMVP		0.55
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137853276; hg19: chr1-171605589;