1-167787822-C-G

Variant names:

• chr1-167787822-C-G
• rs777080906
• ENST00000474859.5:c.608C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_024569.5(MPZL1):​c.608C>G​(p.Ala203Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,610,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A203A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: MPZL1 NM_024569.5 missense, splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.00

Genes affected

MPZL1 (HGNC:7226): (myelin protein zero like 1) Predicted to enable structural molecule activity. Predicted to be involved in cell-cell signaling and transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within positive regulation of cell migration. Located in cell surface and focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25135013).
• BP6: Variant 1-167787822-C-G is Benign according to our data. Variant chr1-167787822-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2553257.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZL1	NM_003953.6	c.711C>G	p.Gly237Gly	splice_region_variant, synonymous_variant	Exon 6 of 6	ENST00000359523.7	NP_003944.1
MPZL1	NM_024569.5	c.608C>G	p.Ala203Gly	missense_variant, splice_region_variant	Exon 5 of 5		NP_078845.3
MPZL1	NM_001146191.2	c.261C>G	p.Gly87Gly	splice_region_variant, synonymous_variant	Exon 3 of 3		NP_001139663.1
MPZL1	XM_047433610.1	c.339C>G	p.Gly113Gly	splice_region_variant, synonymous_variant	Exon 7 of 7		XP_047289566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPZL1	ENST00000359523.7	c.711C>G	p.Gly237Gly	splice_region_variant, synonymous_variant	Exon 6 of 6	1	NM_003953.6	ENSP00000352513.2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000877 AC: 22 AN: 250774 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135526

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000596 AC: 87 AN: 1458666 Hom.: 0 Cov.: 30 AF XY: 0.0000579 AC XY: 42 AN XY: 725924

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.0000505

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 31, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	.;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.36	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Pathogenic	1.1	D
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.035	D;D
Sift4G	Benign	0.40	T;T
Polyphen		1.0	D;.
Vest4		0.34
MVP		0.99
ClinPred		0.21	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs777080906; hg19: chr1-167757059;