NM_001080467.3:c.376A>G

Variant names:

• chr18-50036929-T-C
• rs1815930
• NM_001080467.3:c.376A>G

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.376A>G​(p.Thr126Ala) variant causes a missense change. The variant allele was found at a frequency of 0.996 in 1,614,124 control chromosomes in the GnomAD database, including 800,410 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T126S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.98 (72866 hom., cov: 31)
  • Exomes 𝑓: 1.0 (727544 hom.)
• Consequence: MYO5B NM_001080467.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.18
• Publications: 35 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=9.517018E-7).
• BP6: Variant 18-50036929-T-C is Benign according to our data. Variant chr18-50036929-T-C is described in ClinVar as Benign. ClinVar VariationId is 327087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.376A>G	p.Thr126Ala	missense	Exon 4 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.376A>G	p.Thr126Ala	missense	Exon 4 of 40	ENSP00000285039.6
	MYO5B	ENST00000697219.1		c.172A>G	p.Thr58Ala	missense	Exon 2 of 38	ENSP00000513188.1
	MYO5B	ENST00000908785.1		c.376A>G	p.Thr126Ala	missense	Exon 4 of 28	ENSP00000578844.1

Frequencies

GnomAD3 genomes AF: 0.978 AC: 148738 AN: 152122 Hom.: 72810 Cov.: 31

Gnomad AFR AF: 0.923

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.983

GnomAD2 exomes AF: 0.994 AC: 248169 AN: 249558 AF XY: 0.996

Gnomad AFR exome AF: 0.923

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.998 AC: 1458388 AN: 1461884 Hom.: 727544 Cov.: 52 AF XY: 0.998 AC XY: 725743 AN XY: 727242

African (AFR) AF: 0.922 AC: 30869 AN: 33480

American (AMR) AF: 0.996 AC: 44563 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86235 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53420 AN: 53420

Middle Eastern (MID) AF: 0.995 AC: 5742 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111659 AN: 1112004

Other (OTH) AF: 0.995 AC: 60064 AN: 60396

GnomAD4 genome AF: 0.978 AC: 148852 AN: 152240 Hom.: 72866 Cov.: 31 AF XY: 0.979 AC XY: 72837 AN XY: 74428

African (AFR) AF: 0.923 AC: 38321 AN: 41506

American (AMR) AF: 0.992 AC: 15173 AN: 15298

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5172

South Asian (SAS) AF: 1.00 AC: 4819 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10612 AN: 10612

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67998 AN: 68038

Other (OTH) AF: 0.983 AC: 2081 AN: 2116

Alfa AF: 0.991 Hom.: 148853

Bravo AF: 0.975

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.931 AC: 3738

ESP6500EA AF: 0.999 AC: 8352

ExAC AF: 0.993 AC: 120012

Asia WGS AF: 0.997 AC: 3467 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 1.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Congenital microvillous atrophy (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.68
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.2	N
PhyloP100		6.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	2.8	N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.095
MPC		0.14
ClinPred		0.0037	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.13
gMVP		0.33
Mutation Taster		=96/4	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: rs1815930; hg19: chr18-47563299; COSMIC: COSV107248766; COSMIC: COSV107248766;