chr18-76990036-C-T

Position:

• chr18-76990036-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001025101.2(MBP):​c.601G>A​(p.Ala201Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,612,704 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (104 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (98 hom.)
• Consequence: MBP NM_001025101.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.604

Genes affected

MBP (HGNC:6925): (myelin basic protein) The protein encoded by the classic MBP gene is a major constituent of the myelin sheath of oligodendrocytes and Schwann cells in the nervous system. However, MBP-related transcripts are also present in the bone marrow and the immune system. These mRNAs arise from the long MBP gene (otherwise called "Golli-MBP") that contains 3 additional exons located upstream of the classic MBP exons. Alternative splicing from the Golli and the MBP transcription start sites gives rise to 2 sets of MBP-related transcripts and gene products. The Golli mRNAs contain 3 exons unique to Golli-MBP, spliced in-frame to 1 or more MBP exons. They encode hybrid proteins that have N-terminal Golli aa sequence linked to MBP aa sequence. The second family of transcripts contain only MBP exons and produce the well characterized myelin basic proteins. This complex gene structure is conserved among species suggesting that the MBP transcription unit is an integral part of the Golli transcription unit and that this arrangement is important for the function and/or regulation of these genes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00181216).
• BP6: Variant 18-76990036-C-T is Benign according to our data. Variant chr18-76990036-C-T is described in ClinVar as [Benign]. Clinvar id is 768944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.069 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBP	NM_001025101.2	c.601G>A	p.Ala201Thr	missense_variant	5/9	ENST00000355994.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBP	ENST00000355994.7	c.601G>A	p.Ala201Thr	missense_variant	5/9	5	NM_001025101.2	P1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3163 AN: 152102 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0713

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00585 AC: 1468 AN: 250832 Hom.: 45 AF XY: 0.00452 AC XY: 613 AN XY: 135556

Gnomad AFR exome AF: 0.0751

Gnomad AMR exome AF: 0.00461

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00233 AC: 3400 AN: 1460484 Hom.: 98 Cov.: 31 AF XY: 0.00200 AC XY: 1452 AN XY: 726508

Gnomad4 AFR exome AF: 0.0769

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.00542

GnomAD4 genome AF: 0.0208 AC: 3163 AN: 152220 Hom.: 104 Cov.: 32 AF XY: 0.0200 AC XY: 1488 AN XY: 74434

Gnomad4 AFR AF: 0.0712

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00496 Hom.: 45

Bravo AF: 0.0250

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0715 AC: 315

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00713 AC: 866

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.040
DANN	Benign	0.27
DEOGEN2	Benign	0.065	.;T;T;.;.;T;.;T;T;T;.;T;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;.;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.55	.;N;.;.;.;.;.;.;.;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.49	N;N;N;N;N;N;N;N;N;.;.;.;N;.;N
REVEL	Benign	0.048
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;.;.;.;T;.;T
Sift4G	Benign	0.89	T;T;T;T;T;T;T;T;T;T;T;T;.;.;.
Polyphen		0.0	B;B;.;.;B;.;B;.;.;B;.;.;.;.;.
Vest4		0.085
MVP		0.50
ClinPred		0.012	T
GERP RS		-5.2
Varity_R		0.028

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

Publications

LitVar

Other links and lift over

dbSNP: rs114952201; hg19: chr18-74701992;