rs17659179

Variant names:

• chr18-49984743-C-A
• rs17659179
• NM_001080467.3:c.921G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080467.3(MYO5B):​c.921G>T​(p.Lys307Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 1,612,904 control chromosomes in the GnomAD database, including 2,840 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (192 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2648 hom.)
• Consequence: MYO5B NM_001080467.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.13
• Publications: 21 publications found

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]

MYO5B Gene-Disease associations (from GenCC):

• microvillus inclusion disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• cholestasis, progressive familial intrahepatic, 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial intrahepatic cholestasis type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015074998).
• BP6: Variant 18-49984743-C-A is Benign according to our data. Variant chr18-49984743-C-A is described in ClinVar as Benign. ClinVar VariationId is 327075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080467.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5B	NM_001080467.3	MANE Select	c.921G>T	p.Lys307Asn	missense	Exon 8 of 40	NP_001073936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5B	ENST00000285039.12	TSL:1 MANE Select	c.921G>T	p.Lys307Asn	missense	Exon 8 of 40	ENSP00000285039.6
	MYO5B	ENST00000697219.1		c.717G>T	p.Lys239Asn	missense	Exon 6 of 38	ENSP00000513188.1

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7032 AN: 152134 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0407

Gnomad EAS AF: 0.00926

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0635

Gnomad OTH AF: 0.0450

GnomAD2 exomes AF: 0.0515 AC: 12845 AN: 249500 AF XY: 0.0514

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0670

Gnomad ASJ exome AF: 0.0475

Gnomad EAS exome AF: 0.00879

Gnomad FIN exome AF: 0.0491

Gnomad NFE exome AF: 0.0633

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0576 AC: 84171 AN: 1460652 Hom.: 2648 Cov.: 31 AF XY: 0.0569 AC XY: 41341 AN XY: 726724

African (AFR) AF: 0.0181 AC: 606 AN: 33456

American (AMR) AF: 0.0636 AC: 2843 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0475 AC: 1241 AN: 26130

East Asian (EAS) AF: 0.00544 AC: 216 AN: 39696

South Asian (SAS) AF: 0.0330 AC: 2842 AN: 86236

European-Finnish (FIN) AF: 0.0531 AC: 2838 AN: 53420

Middle Eastern (MID) AF: 0.0380 AC: 219 AN: 5764

European-Non Finnish (NFE) AF: 0.0634 AC: 70472 AN: 1110870

Other (OTH) AF: 0.0479 AC: 2894 AN: 60360

GnomAD4 genome AF: 0.0462 AC: 7031 AN: 152252 Hom.: 192 Cov.: 32 AF XY: 0.0453 AC XY: 3375 AN XY: 74452

African (AFR) AF: 0.0196 AC: 813 AN: 41554

American (AMR) AF: 0.0532 AC: 814 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 141 AN: 3468

East Asian (EAS) AF: 0.00928 AC: 48 AN: 5172

South Asian (SAS) AF: 0.0268 AC: 129 AN: 4822

European-Finnish (FIN) AF: 0.0536 AC: 569 AN: 10606

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0635 AC: 4317 AN: 68018

Other (OTH) AF: 0.0441 AC: 93 AN: 2110

Alfa AF: 0.0551 Hom.: 731

Bravo AF: 0.0446

ESP6500AA AF: 0.0188 AC: 75

ESP6500EA AF: 0.0577 AC: 482

ExAC AF: 0.0511 AC: 6174

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital microvillous atrophy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.015	N
PhyloP100		1.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.32
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.0040	B
Vest4		0.59
MutPred		0.23		Loss of ubiquitination at K307 (P = 0.0297)
MPC		0.69
ClinPred		0.013	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.55
Mutation Taster		=77/23	polymorphism (auto)

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: rs17659179; hg19: chr18-47511113; COSMIC: COSV107248954;