11-61770355-A-C

Variant names:

• chr11-61770355-A-C
• rs780504743
• NM_001127392.3:c.570A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001127392.3(MYRF):​c.570A>C​(p.Pro190Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYRF NM_001127392.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.59
• Publications: 0 publications found

Genes affected

MYRF (HGNC:1181): (myelin regulatory factor) This gene encodes a transcription factor that is required for central nervous system myelination and may regulate oligodendrocyte differentiation. It is thought to act by increasing the expression of genes that effect myelin production but may also directly promote myelin gene expression. Loss of a similar gene in mouse models results in severe demyelination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

TMEM258 (HGNC:1164): (transmembrane protein 258) Involved in protein N-linked glycosylation. Located in endoplasmic reticulum. Part of oligosaccharyltransferase I complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-61770355-A-C is Benign according to our data. Variant chr11-61770355-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3037556.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127392.3. 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
	MYRF	NM_001127392.3	MANE Select	c.570A>C	p.Pro190Pro	synonymous	Exon 5 of 27	NP_001120864.1	Q9Y2G1-1
	MYRF	NM_013279.4		c.543A>C	p.Pro181Pro	synonymous	Exon 5 of 26	NP_037411.1	Q9Y2G1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYRF	ENST00000278836.10	TSL:1 MANE Select	c.570A>C	p.Pro190Pro	synonymous	Exon 5 of 27	ENSP00000278836.4	Q9Y2G1-1
	MYRF	ENST00000265460.9	TSL:1	c.543A>C	p.Pro181Pro	synonymous	Exon 5 of 26	ENSP00000265460.5	Q9Y2G1-2
	MYRF	ENST00000856811.1		c.570A>C	p.Pro190Pro	synonymous	Exon 5 of 27	ENSP00000526870.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 706 AN: 41122 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.0381

Gnomad AMR AF: 0.00930

Gnomad ASJ AF: 0.0166

Gnomad EAS AF: 0.00326

Gnomad SAS AF: 0.0123

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0691 AC: 2665 AN: 38572 AF XY: 0.0697

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.0806

Gnomad ASJ exome AF: 0.0528

Gnomad EAS exome AF: 0.0563

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.0446

Gnomad OTH exome AF: 0.0605

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0481 AC: 7959 AN: 165614 Hom.: 0 Cov.: 10 AF XY: 0.0494 AC XY: 4115 AN XY: 83290

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0379 AC: 146 AN: 3850

American (AMR) AF: 0.0918 AC: 525 AN: 5722

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 138 AN: 3402

East Asian (EAS) AF: 0.0823 AC: 230 AN: 2794

South Asian (SAS) AF: 0.0809 AC: 1157 AN: 14308

European-Finnish (FIN) AF: 0.0746 AC: 512 AN: 6860

Middle Eastern (MID) AF: 0.0399 AC: 22 AN: 552

European-Non Finnish (NFE) AF: 0.0407 AC: 4949 AN: 121728

Other (OTH) AF: 0.0438 AC: 280 AN: 6398

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0171 AC: 704 AN: 41114 Hom.: 0 Cov.: 0 AF XY: 0.0150 AC XY: 313 AN XY: 20902

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0165 AC: 177 AN: 10716

American (AMR) AF: 0.00927 AC: 50 AN: 5394

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 15 AN: 906

East Asian (EAS) AF: 0.00327 AC: 5 AN: 1528

South Asian (SAS) AF: 0.0114 AC: 11 AN: 968

European-Finnish (FIN) AF: 0.0183 AC: 58 AN: 3172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 158

European-Non Finnish (NFE) AF: 0.0214 AC: 371 AN: 17364

Other (OTH) AF: 0.0129 AC: 9 AN: 698

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0106 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	MYRF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.1
DANN	Benign	0.62
PhyloP100		-3.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs780504743; hg19: chr11-61537827; COSMIC: COSV53886682; COSMIC: COSV53886682;