18-49849562-C-G

Position:

• chr18-49849562-C-G

Variant summary

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

The NM_001080467.3(MYO5B):​c.4315+5G>C variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,599,336 control chromosomes in the GnomAD database, including 171,694 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15407 hom., cov: 32)
  • Exomes 𝑓: 0.46 (156287 hom.)
• Consequence: MYO5B NM_001080467.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.09528
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.32

Genes affected

MYO5B (HGNC:7603): (myosin VB) The protein encoded by this gene, together with other proteins, may be involved in plasma membrane recycling. Mutations in this gene are associated with microvillous inclusion disease. [provided by RefSeq, Sep 2009]

SNHG22 (HGNC:50285): (small nucleolar RNA host gene 22)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 18-49849562-C-G is Benign according to our data. Variant chr18-49849562-C-G is described in ClinVar as [Benign]. Clinvar id is 327014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-49849562-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO5B	NM_001080467.3	c.4315+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000285039.12
SNHG22	NR_117096.1	n.193-75C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO5B	ENST00000285039.12	c.4315+5G>C		splice_donor_5th_base_variant, intron_variant		1	NM_001080467.3	P1
SNHG22	ENST00000589499.1	n.193-75C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67179 AN: 151942 Hom.: 15410 Cov.: 32

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.478

GnomAD3 exomes AF: 0.402 AC: 100225 AN: 249532 Hom.: 22136 AF XY: 0.409 AC XY: 55416 AN XY: 135386

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.549

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.336

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.436

GnomAD4 exome AF: 0.456 AC: 660342 AN: 1447276 Hom.: 156287 Cov.: 30 AF XY: 0.455 AC XY: 327787 AN XY: 720826

Gnomad4 AFR exome AF: 0.442

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.553

Gnomad4 EAS exome AF: 0.122

Gnomad4 SAS exome AF: 0.334

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.487

Gnomad4 OTH exome AF: 0.443

GnomAD4 genome AF: 0.442 AC: 67189 AN: 152060 Hom.: 15407 Cov.: 32 AF XY: 0.434 AC XY: 32271 AN XY: 74312

Gnomad4 AFR AF: 0.437

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.554

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.492

Gnomad4 OTH AF: 0.474

Alfa AF: 0.450 Hom.: 4598

Bravo AF: 0.440

Asia WGS AF: 0.260 AC: 905 AN: 3478

EpiCase AF: 0.502

EpiControl AF: 0.510

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital microvillous atrophy Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.037
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.095
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.16		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: rs488890; hg19: chr18-47375932; COSMIC: COSV53217485;