18-49929610-GAAAAAAA-GAAAA

Variant names:

• chr18-49929610-GAAA-G
• rs56278513
• NM_001080467.3:c.2004-15_2004-13delTTT

Variant summary

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

The NM_001080467.3(MYO5B):​c.2004-15_2004-13delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,260,590 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0049 (0 hom.)
• Consequence: MYO5B NM_001080467.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.00646) population. However there is too low homozygotes in high coverage region: (expected more than 5, got 0).

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.2004-15_2004-13delTTT		intron	N/A	NP_001073936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5B	ENST00000285039.12	TSL:1 MANE Select	c.2004-15_2004-13delTTT		intron	N/A	ENSP00000285039.6
	MYO5B	ENST00000697219.1		c.1800-15_1800-13delTTT		intron	N/A	ENSP00000513188.1

Frequencies

GnomAD3 genomes AF: 0.0000602 AC: 8 AN: 132848 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000145

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000480

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00734 AC: 840 AN: 114366 AF XY: 0.00712

Gnomad AFR exome AF: 0.00579

Gnomad AMR exome AF: 0.00885

Gnomad ASJ exome AF: 0.00402

Gnomad EAS exome AF: 0.00755

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00675

GnomAD4 exome AF: 0.00487 AC: 5489 AN: 1127764 Hom.: 0 AF XY: 0.00455 AC XY: 2565 AN XY: 563876

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00531 AC: 138 AN: 25970

American (AMR) AF: 0.00723 AC: 227 AN: 31410

Ashkenazi Jewish (ASJ) AF: 0.00378 AC: 82 AN: 21686

East Asian (EAS) AF: 0.00341 AC: 111 AN: 32526

South Asian (SAS) AF: 0.00421 AC: 291 AN: 69158

European-Finnish (FIN) AF: 0.00467 AC: 165 AN: 35338

Middle Eastern (MID) AF: 0.00381 AC: 13 AN: 3412

European-Non Finnish (NFE) AF: 0.00492 AC: 4235 AN: 860514

Other (OTH) AF: 0.00475 AC: 227 AN: 47750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000602 AC: 8 AN: 132826 Hom.: 0 Cov.: 0 AF XY: 0.0000630 AC XY: 4 AN XY: 63444

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000564 AC: 2 AN: 35460

American (AMR) AF: 0.000152 AC: 2 AN: 13142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3244

East Asian (EAS) AF: 0.00 AC: 0 AN: 4606

South Asian (SAS) AF: 0.00 AC: 0 AN: 4060

European-Finnish (FIN) AF: 0.000145 AC: 1 AN: 6884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.0000480 AC: 3 AN: 62516

Other (OTH) AF: 0.00 AC: 0 AN: 1816

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00965 Hom.: 142

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

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: rs56278513; hg19: chr18-47455980;