1-167765685-C-T

Variant names:

• chr1-167765685-C-T
• rs774611276
• NM_003953.6:c.194C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003953.6(MPZL1):​c.194C>T​(p.Thr65Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,210 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 (★). Synonymous variant affecting the same amino acid position (i.e. T65T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MPZL1 NM_003953.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.783
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.107019484).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003953.6. 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
	MPZL1	NM_003953.6	MANE Select	c.194C>T	p.Thr65Met	missense	Exon 2 of 6	NP_003944.1	A8K5D4
	MPZL1	NM_024569.5		c.194C>T	p.Thr65Met	missense	Exon 2 of 5	NP_078845.3
	MPZL1	NM_001146191.2		c.194C>T	p.Thr65Met	missense	Exon 2 of 3	NP_001139663.1	O95297-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPZL1	ENST00000359523.7	TSL:1 MANE Select	c.194C>T	p.Thr65Met	missense	Exon 2 of 6	ENSP00000352513.2	O95297-1
	MPZL1	ENST00000474859.5	TSL:1	c.194C>T	p.Thr65Met	missense	Exon 2 of 5	ENSP00000420455.1	O95297-3
	MPZL1	ENST00000367853.3	TSL:1	c.116C>T	p.Thr39Met	missense	Exon 1 of 4	ENSP00000356827.3	Q9UEL6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250560 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461024 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726832

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111534

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

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

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ 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: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000594

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	0.074
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.3
DANN	Benign	0.56
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.78
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.13
Sift	Benign	0.10	T
Sift4G	Benign	0.26	T
Polyphen		0.036	B
Vest4		0.11
MutPred		0.45		Loss of catalytic residue at T65 (P = 0.0481)
MVP		0.88
MPC		0.45
ClinPred		0.030	T
GERP RS		-3.6
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.25
Mutation Taster		=86/14	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: rs774611276; hg19: chr1-167734922; COSMIC: COSV105257550;