Genetic Variant MYO7B:p.Glu1673Asp (chr2-127631287-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001393586.1(MYO7B):c.5019G>T(p.Glu1673Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1673K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MYO7B
NM_001393586.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.24

Publications

26 publications found

Variant links:

Genes affected

MYO7B (HGNC:7607): (myosin VIIB) The protein encoded by this gene is found in brush border microvilli of epithelial cells in the intestines and kidneys. The encoded protein is involved in linking protocadherins to the actin cytoskeleton and is essential for proper microvilli function. This protein aids in the accumulation of intermicrovillar adhesion components such as harmonin and ANKS4B, and this accumulation is necessary for normal brush border action. [provided by RefSeq, Jan 2017]

MYO7B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393586.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYO7B	NM_001393586.1	MANE Select	c.5019G>T	p.Glu1673Asp	missense	Exon 37 of 48	NP_001380515.1
MYO7B	NM_001080527.2		c.4941G>T	p.Glu1647Asp	missense	Exon 36 of 47	NP_001073996.1
MYO7B	NM_001393594.1		c.1500G>T	p.Glu500Asp	missense	Exon 12 of 23	NP_001380523.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYO7B	ENST00000409816.8	TSL:1 MANE Select	c.5019G>T	p.Glu1673Asp	missense	Exon 37 of 48	ENSP00000386461.3
MYO7B	ENST00000409090.1	TSL:1	c.1500G>T	p.Glu500Asp	missense	Exon 12 of 23	ENSP00000386850.1
MYO7B	ENST00000496841.5	TSL:1	n.1963G>T		non_coding_transcript_exon	Exon 11 of 19

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459582

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111260

Other (OTH)

AF:

0.00

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

Eigen

Benign

0.053

Eigen_PC

Benign

0.085

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.83

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.2

PhyloP100

2.2

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.17

Sift

Benign

0.20

Sift4G

Benign

0.086

Polyphen

0.85

Vest4

0.36

MutPred

0.25

Loss of phosphorylation at Y1644 (P = 0.1769)

MVP

0.54

MPC

0.28

ClinPred

0.94

GERP RS

4.9

Varity_R

0.27

gMVP

0.38

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over