Genetic Variant NM_022362.5:c.2561G>T (chr10-97460141-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_022362.5(MMS19):c.2561G>T(p.Arg854Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R854H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MMS19
NM_022362.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.63

Publications

3 publications found

Variant links:

Genes affected

MMS19 (HGNC:13824): (MMS19 homolog, cytosolic iron-sulfur assembly component) Enables estrogen receptor binding activity and transcription coactivator activity. Involved in several processes, including iron-sulfur cluster assembly; positive regulation of nucleobase-containing compound metabolic process; and protein maturation by iron-sulfur cluster transfer. Located in cytosol; nucleoplasm; and spindle. Part of CIA complex and MMXD complex. [provided by Alliance of Genome Resources, Apr 2022]

MMS19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BS2

High AC in GnomAdExome4 at 50 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022362.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMS19	NM_022362.5	MANE Select	c.2561G>T	p.Arg854Leu	missense	Exon 26 of 31	NP_071757.4
MMS19	NM_001351356.2		c.2678G>T	p.Arg893Leu	missense	Exon 27 of 32	NP_001338285.1
MMS19	NM_001289405.2		c.2561G>T	p.Arg854Leu	missense	Exon 27 of 32	NP_001276334.1	Q96T76-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMS19	ENST00000438925.7	TSL:1 MANE Select	c.2561G>T	p.Arg854Leu	missense	Exon 26 of 31	ENSP00000412698.2	Q96T76-1
MMS19	ENST00000370782.6	TSL:1	c.2561G>T	p.Arg854Leu	missense	Exon 27 of 32	ENSP00000359818.1	Q96T76-1
MMS19	ENST00000355839.10	TSL:1	c.2432G>T	p.Arg811Leu	missense	Exon 25 of 30	ENSP00000348097.6	Q96T76-9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000479

AC:

AN:

250644

AF XY:

0.0000664

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 FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000487

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111850

Other (OTH)

AF:

0.0000331

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000741

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.053

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.3

PhyloP100

3.6

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.22

Sift

Uncertain

0.023

Sift4G

Uncertain

0.0090

Polyphen

0.12

Vest4

0.71

MutPred

0.48

Loss of solvent accessibility (P = 0.0299)

MVP

0.67

MPC

0.19

ClinPred

0.58

GERP RS

5.3

PromoterAI

-0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.32

gMVP

0.36

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over