Genetic Variant NM_001163629.2:c.581T>C (chr1-170971848-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001163629.2(MROH9):c.581T>C(p.Met194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

MROH9
NM_001163629.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.58

Variant links:

Genes affected

MROH9 (HGNC:26287): (maestro heat like repeat family member 9)

MROH9 links:

ENSG00000231424 (HGNC:40240):

ENSG00000231424 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MROH9	NM_001163629.2 link	c.581T>C	p.Met194Thr	missense_variant	Exon 8 of 22	ENST00000367759.9	NP_001157101.1	Q5TGP6-2
MROH9	NM_025063.4 link	c.581T>C	p.Met194Thr	missense_variant	Exon 8 of 15		NP_079339.2	Q5TGP6-1
MROH9	XM_011510005.3 link	c.581T>C	p.Met194Thr	missense_variant	Exon 8 of 21		XP_011508307.1
MROH9	XM_011510006.3 link	c.581T>C	p.Met194Thr	missense_variant	Exon 8 of 21		XP_011508308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MROH9	ENST00000367759.9 link	c.581T>C	p.Met194Thr	missense_variant	Exon 8 of 22	5	NM_001163629.2	ENSP00000356733.4		Q5TGP6-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249416

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135308

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000965

AC:

141

AN:

1461766

Hom.:

Cov.:

AF XY:

0.0000976

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.581T>C (p.M194T) alteration is located in exon 8 (coding exon 7) of the MROH9 gene. This alteration results from a T to C substitution at nucleotide position 581, causing the methionine (M) at amino acid position 194 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0088

.;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.069

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.067

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.26

Sift

Benign

0.098

T;T

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.99

.;D

Vest4

0.78

MVP

0.75

MPC

0.26

ClinPred

0.64

GERP RS

5.3

Varity_R

0.25

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over