2-127631287-G-T

Variant names:

• chr2-127631287-G-T
• rs13025959
• NM_001393586.1:c.5019G>T

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• Publications: 26 publications found

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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7B	NM_001393586.1	c.5019G>T	p.Glu1673Asp	missense_variant	Exon 37 of 48	ENST00000409816.8	NP_001380515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7B	ENST00000409816.8	c.5019G>T	p.Glu1673Asp	missense_variant	Exon 37 of 48	1	NM_001393586.1	ENSP00000386461.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459582 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 725980

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111260

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T;T
Eigen	Benign	0.053
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T;.;T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		2.2
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.086	T;T;T
Polyphen		0.85	P;P;.
Vest4		0.36
MutPred		0.25		Loss of phosphorylation at Y1644 (P = 0.1769);Loss of phosphorylation at Y1644 (P = 0.1769);.;
MVP		0.54
MPC		0.28
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.27
gMVP		0.38
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs13025959; hg19: chr2-128388862;