NM_001080467.3:c.3962G>A

Variant names:

• chr18-49856873-C-T
• rs1942418
• NM_001080467.3:c.3962G>A

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.3962G>A​(p.Gly1321Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0723 in 1,613,512 control chromosomes in the GnomAD database, including 9,225 homozygotes. In-silico tool predicts 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. G1321R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.079 (955 hom., cov: 33)
  • Exomes 𝑓: 0.072 (8270 hom.)
• Consequence: MYO5B NM_001080467.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.59
• Publications: 22 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, 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=0.0016974807).
• BP6: Variant 18-49856873-C-T is Benign according to our data. Variant chr18-49856873-C-T is described in ClinVar as Benign. ClinVar VariationId is 327017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5B	NM_001080467.3	MANE Select	c.3962G>A	p.Gly1321Glu	missense	Exon 30 of 40	NP_001073936.1	Q9ULV0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5B	ENST00000285039.12	TSL:1 MANE Select	c.3962G>A	p.Gly1321Glu	missense	Exon 30 of 40	ENSP00000285039.6	Q9ULV0-1
	MYO5B	ENST00000697219.1		c.3695G>A	p.Gly1232Glu	missense	Exon 28 of 38	ENSP00000513188.1	A0A8V8TM52
	MYO5B	ENST00000697217.1		c.326G>A	p.Gly109Glu	missense	Exon 4 of 14	ENSP00000513187.1	A0A8V8TKV2

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12062 AN: 152190 Hom.: 946 Cov.: 33

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0562

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0894

GnomAD2 exomes AF: 0.121 AC: 30124 AN: 249452 AF XY: 0.108

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.0448

Gnomad EAS exome AF: 0.293

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0478

Gnomad OTH exome AF: 0.0933

GnomAD4 exome AF: 0.0715 AC: 104540 AN: 1461204 Hom.: 8270 Cov.: 31 AF XY: 0.0710 AC XY: 51598 AN XY: 726946

African (AFR) AF: 0.0553 AC: 1849 AN: 33460

American (AMR) AF: 0.365 AC: 16339 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 1129 AN: 26134

East Asian (EAS) AF: 0.361 AC: 14315 AN: 39690

South Asian (SAS) AF: 0.103 AC: 8917 AN: 86226

European-Finnish (FIN) AF: 0.0569 AC: 3038 AN: 53406

Middle Eastern (MID) AF: 0.0827 AC: 477 AN: 5766

European-Non Finnish (NFE) AF: 0.0485 AC: 53915 AN: 1111440

Other (OTH) AF: 0.0755 AC: 4561 AN: 60372

GnomAD4 genome AF: 0.0794 AC: 12094 AN: 152308 Hom.: 955 Cov.: 33 AF XY: 0.0840 AC XY: 6257 AN XY: 74464

African (AFR) AF: 0.0547 AC: 2276 AN: 41576

American (AMR) AF: 0.230 AC: 3520 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3468

East Asian (EAS) AF: 0.296 AC: 1535 AN: 5178

South Asian (SAS) AF: 0.113 AC: 545 AN: 4830

European-Finnish (FIN) AF: 0.0562 AC: 595 AN: 10596

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0478 AC: 3251 AN: 68034

Other (OTH) AF: 0.0903 AC: 191 AN: 2114

Alfa AF: 0.0638 Hom.: 2710

Bravo AF: 0.0957

TwinsUK AF: 0.0499 AC: 185

ALSPAC AF: 0.0519 AC: 200

ESP6500AA AF: 0.0482 AC: 184

ESP6500EA AF: 0.0517 AC: 427

ExAC AF: 0.109 AC: 13137

Asia WGS AF: 0.177 AC: 613 AN: 3478

EpiCase AF: 0.0492

EpiControl AF: 0.0483

ClinVar

ClinVar submissions

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	Uncertain	0.35
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.025
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.081
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.049	B
Vest4		0.37
MPC		0.71
ClinPred		0.024	T
GERP RS		5.3
Varity_R		0.19
gMVP		0.61
Mutation Taster		=54/46	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: rs1942418; hg19: chr18-47383243; COSMIC: COSV53213017;