20-64105913-C-T

Variant names:

• chr20-64105913-C-T
• rs748131572
• NM_005286.4:c.919G>A

Variant summary

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

The NM_005286.4(NPBWR2):​c.919G>A​(p.Ala307Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,607,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: NPBWR2 NM_005286.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.794
• Publications: 3 publications found

Genes affected

NPBWR2 (HGNC:4530): (neuropeptides B and W receptor 2) The protein encoded by this gene is an integral membrane protein and G protein-coupled receptor. The encoded protein is similar in sequence to another G protein-coupled receptor (GPR7), and it is structurally similar to opioid and somatostatin receptors. This protein binds neuropeptides B and W. This gene is intronless and is expressed primarily in the frontal cortex of the brain. [provided by RefSeq, Jul 2008]

MYT1 (HGNC:7622): (myelin transcription factor 1) The protein encoded by this gene is a member of a family of neural specific, zinc finger-containing DNA-binding proteins. The protein binds to the promoter regions of proteolipid proteins of the central nervous system and plays a role in the developing nervous system. [provided by RefSeq, Jul 2008]

MYT1 Gene-Disease associations (from GenCC):

• craniofacial microsomia

  Inheritance: AD Classification: LIMITED Submitted by: G2P

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=0.22704479).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005286.4. 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
	NPBWR2	NM_005286.4	MANE Select	c.919G>A	p.Ala307Thr	missense	Exon 2 of 2	NP_005277.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPBWR2	ENST00000684052.1	MANE Select	c.919G>A	p.Ala307Thr	missense	Exon 2 of 2	ENSP00000508236.1	P48146
	NPBWR2	ENST00000369768.1	TSL:6	c.919G>A	p.Ala307Thr	missense	Exon 1 of 1	ENSP00000358783.1	P48146
	MYT1	ENST00000928401.1		c.-570+3358C>T		intron	N/A	ENSP00000598460.1

Frequencies

GnomAD3 genomes AF: 0.00000671 AC: 1 AN: 148924 Hom.: 0 Cov.: 30

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: 0.00

Gnomad OTH AF: 0.000491

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250180 AF XY: 0.00000737

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1458332 Hom.: 0 Cov.: 35 AF XY: 0.0000165 AC XY: 12 AN XY: 725530

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1110214

Other (OTH) AF: 0.0000498 AC: 3 AN: 60220

GnomAD4 genome AF: 0.00000671 AC: 1 AN: 148924 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 1 AN XY: 72588

⚠️ 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: 41042

American (AMR) AF: 0.00 AC: 0 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66512

Other (OTH) AF: 0.000491 AC: 1 AN: 2038

⚠️ 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: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

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	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.73
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.79
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.059
Sift	Benign	0.044	D
Sift4G	Benign	0.27	T
Polyphen		0.26	B
Vest4		0.093
MutPred		0.59		Loss of helix (P = 0.2022)
MVP		0.56
MPC		0.24
ClinPred		0.14	T
GERP RS		0.19
Varity_R		0.15
gMVP		0.42
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs748131572; hg19: chr20-62737266; COSMIC: COSV63900129;