chr1-171635594-T-C

Variant names:

• chr1-171635594-T-C
• rs548121911
• NM_000261.2:c.*331A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BS1_Supporting BS2_Supporting

The NM_000261.2(MYOC):​c.*331A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000811 in 450,192 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: MYOC NM_000261.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -2.28
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000263 (40/152370) while in subpopulation SAS AF = 0.00827 (40/4834). AF 95% confidence interval is 0.00625. There are 1 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 40 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000261.2. 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
	MYOC	NM_000261.2	MANE Select	c.*331A>G		3_prime_UTR	Exon 3 of 3	NP_000252.1	Q99972

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOC	ENST00000037502.11	TSL:1 MANE Select	c.*331A>G		3_prime_UTR	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.*331A>G		3_prime_UTR	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.*331A>G		3_prime_UTR	Exon 4 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152252 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00109 AC: 325 AN: 297822 Hom.: 4 Cov.: 0 AF XY: 0.00159 AC XY: 246 AN XY: 154456

African (AFR) AF: 0.0000988 AC: 1 AN: 10126

American (AMR) AF: 0.00 AC: 0 AN: 13434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10328

East Asian (EAS) AF: 0.00 AC: 0 AN: 20544

South Asian (SAS) AF: 0.00878 AC: 318 AN: 36232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 176652

Other (OTH) AF: 0.000336 AC: 6 AN: 17832

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152370 Hom.: 1 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74524

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00827 AC: 40 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000567

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glaucoma (1)
-	1	-	Glaucoma 1, open angle, A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.097
DANN	Benign	0.62
PhyloP100		-2.3
Mutation Taster		=100/0	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: rs548121911; hg19: chr1-171604734;