chr10-97460113-C-G

Variant names:

• chr10-97460113-C-G
• rs766872182
• NM_022362.5:c.2589G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_022362.5(MMS19):​c.2589G>C​(p.Met863Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: MMS19 NM_022362.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821
• BS2: High AC in GnomAdExome4 at 78 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMS19	NM_022362.5	MANE Select	c.2589G>C	p.Met863Ile	missense	Exon 26 of 31	NP_071757.4
	MMS19	NM_001351356.2		c.2706G>C	p.Met902Ile	missense	Exon 27 of 32	NP_001338285.1
	MMS19	NM_001289405.2		c.2589G>C	p.Met863Ile	missense	Exon 27 of 32	NP_001276334.1	Q96T76-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMS19	ENST00000438925.7	TSL:1 MANE Select	c.2589G>C	p.Met863Ile	missense	Exon 26 of 31	ENSP00000412698.2	Q96T76-1
	MMS19	ENST00000370782.6	TSL:1	c.2589G>C	p.Met863Ile	missense	Exon 27 of 32	ENSP00000359818.1	Q96T76-1
	MMS19	ENST00000355839.10	TSL:1	c.2460G>C	p.Met820Ile	missense	Exon 25 of 30	ENSP00000348097.6	Q96T76-9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250950 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000702 AC: 78 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68052

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.90	P
Vest4		0.92
MutPred		0.46		Gain of sheet (P = 0.039)
MVP		0.80
MPC		0.45
ClinPred		0.86	D
GERP RS		5.7
PromoterAI		0.022	Neutral
Varity_R		0.79
gMVP		0.61
Mutation Taster		=48/52	disease causing

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: rs766872182; hg19: chr10-99219870;