NM_001163735.2:c.2757+541G>A

Variant names:

• chr17-36497725-C-T
• rs140610432
• NM_001163735.2:c.2757+541G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001163735.2(MYO19):​c.2757+541G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 184,406 control chromosomes in the GnomAD database, including 655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.070 (628 hom., cov: 32)
  • Exomes 𝑓: 0.038 (27 hom.)
• Consequence: MYO19 NM_001163735.2 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.303
• Publications: 3 publications found

Genes affected

MYO19 (HGNC:26234): (myosin XIX) Enables actin binding activity. Involved in regulation of cytokinesis and regulation of mitochondrial fission. Acts upstream of or within mitochondrion migration along actin filament. Located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZNHIT3 (HGNC:12309): (zinc finger HIT-type containing 3) Predicted to enable thyroid hormone receptor binding activity. Predicted to be involved in box C/D snoRNP assembly; maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA); and snoRNA localization. Located in cytoplasm and nucleus. Implicated in PEHO syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ZNHIT3 Gene-Disease associations (from GenCC):

• PEHO syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Mayer-Rokitansky-Kuster-Hauser syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.886575).
• BP6: Variant 17-36497725-C-T is Benign according to our data. Variant chr17-36497725-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056481.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163735.2. 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
	MYO19	NM_001163735.2	MANE Select	c.2757+541G>A		intron	N/A	NP_001157207.1	Q96H55-1
	ZNHIT3	NM_001281432.2		c.406C>T	p.Gln136*	stop_gained	Exon 5 of 5	NP_001268361.1	Q15649-2
	MYO19	NM_025109.6		c.2157+541G>A		intron	N/A	NP_079385.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO19	ENST00000614623.5	TSL:2 MANE Select	c.2757+541G>A		intron	N/A	ENSP00000479518.1	Q96H55-1
	MYO19	ENST00000610930.4	TSL:5	c.2157+541G>A		intron	N/A	ENSP00000478437.1	Q96H55-4
	ZNHIT3	ENST00000612728.4	TSL:1	n.396C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10642 AN: 152064 Hom.: 628 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.0191

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0736

GnomAD2 exomes AF: 0.00 AC: 0 AN: 20 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0378 AC: 1217 AN: 32224 Hom.: 27 Cov.: 4 AF XY: 0.0378 AC XY: 596 AN XY: 15776

African (AFR) AF: 0.157 AC: 101 AN: 642

American (AMR) AF: 0.00 AC: 0 AN: 46

Ashkenazi Jewish (ASJ) AF: 0.00971 AC: 2 AN: 206

East Asian (EAS) AF: 0.0224 AC: 3 AN: 134

South Asian (SAS) AF: 0.0116 AC: 7 AN: 602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10

Middle Eastern (MID) AF: 0.0606 AC: 4 AN: 66

European-Non Finnish (NFE) AF: 0.0360 AC: 1061 AN: 29442

Other (OTH) AF: 0.0362 AC: 39 AN: 1076

GnomAD4 genome AF: 0.0701 AC: 10663 AN: 152182 Hom.: 628 Cov.: 32 AF XY: 0.0677 AC XY: 5036 AN XY: 74412

African (AFR) AF: 0.157 AC: 6525 AN: 41470

American (AMR) AF: 0.0474 AC: 725 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3472

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5182

South Asian (SAS) AF: 0.0157 AC: 76 AN: 4832

European-Finnish (FIN) AF: 0.0337 AC: 357 AN: 10604

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0357 AC: 2430 AN: 68012

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0588 Hom.: 46

Bravo AF: 0.0756

ExAC AF: 0.00504 AC: 15

Asia WGS AF: 0.0330 AC: 113 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ZNHIT3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.8
DANN	Benign	0.62
FATHMM_MKL	Benign	0.016	N
PhyloP100		0.30
Vest4		0.033
GERP RS		0.23
Mutation Taster		=181/19	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: rs140610432; hg19: chr17-34853569;