8-143567423-G-A

Variant names:

• chr8-143567423-G-A
• rs746796492
• NM_001100878.2:c.1976C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001100878.2(MROH6):​c.1976C>T​(p.Ala659Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,322,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A659T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: MROH6 NM_001100878.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.128
• Publications: 1 publications found

Genes affected

MROH6 (HGNC:27814): (maestro heat like repeat family member 6)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046218336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MROH6	NM_001100878.2	c.1976C>T	p.Ala659Val	missense_variant	Exon 14 of 14	ENST00000398882.8	NP_001094348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MROH6	ENST00000398882.8	c.1976C>T	p.Ala659Val	missense_variant	Exon 14 of 14	5	NM_001100878.2	ENSP00000381857.3

Frequencies

GnomAD3 genomes AF: 0.000750 AC: 114 AN: 151954 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000193 AC: 3 AN: 15528 AF XY: 0.00

Gnomad AFR exome AF: 0.00366

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000141 AC: 165 AN: 1170334 Hom.: 0 Cov.: 44 AF XY: 0.000153 AC XY: 86 AN XY: 562538

African (AFR) AF: 0.00255 AC: 61 AN: 23904

American (AMR) AF: 0.000451 AC: 5 AN: 11088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15928

East Asian (EAS) AF: 0.00 AC: 0 AN: 27556

South Asian (SAS) AF: 0.000157 AC: 7 AN: 44510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29426

Middle Eastern (MID) AF: 0.000945 AC: 3 AN: 3176

European-Non Finnish (NFE) AF: 0.0000817 AC: 79 AN: 967240

Other (OTH) AF: 0.000210 AC: 10 AN: 47506

GnomAD4 genome AF: 0.000750 AC: 114 AN: 152066 Hom.: 0 Cov.: 36 AF XY: 0.000807 AC XY: 60 AN XY: 74350

African (AFR) AF: 0.00178 AC: 74 AN: 41542

American (AMR) AF: 0.00242 AC: 37 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67906

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000899

ExAC AF: 0.0000593 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1976C>T (p.A659V) alteration is located in exon 14 (coding exon 14) of the MROH6 gene. This alteration results from a C to T substitution at nucleotide position 1976, causing the alanine (A) at amino acid position 659 to be replaced by a valine (V). 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	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.087	N
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.13
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.054
Sift	Benign	0.47	T
Sift4G	Benign	0.064	T
Polyphen		0.66	P
Vest4		0.15
MVP		0.030
MPC		0.053
ClinPred		0.018	T
GERP RS		2.6
Varity_R		0.022
gMVP		0.068
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs746796492; hg19: chr8-144649593;