10-97460966-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_022362.5(MMS19):c.2353G>A(p.Val785Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,422,610 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MMS19 NM_022362.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13132682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMS19	NM_022362.5	c.2353G>A	p.Val785Met	missense_variant	24/31	ENST00000438925.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMS19	ENST00000438925.7	c.2353G>A	p.Val785Met	missense_variant	24/31	1	NM_022362.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000208 AC: 4 AN: 192238 Hom.: 0 AF XY: 0.00000981 AC XY: 1 AN XY: 101962

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: 0.0000408

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.000196

GnomAD4 exome AF: 0.0000232 AC: 33 AN: 1422610 Hom.: 0 Cov.: 32 AF XY: 0.0000256 AC XY: 18 AN XY: 703790

Gnomad4 AFR exome AF: 0.000428

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000733

Gnomad4 OTH exome AF: 0.000136

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000719 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000833 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2021

The c.2353G>A (p.V785M) alteration is located in exon 24 (coding exon 24) of the MMS19 gene. This alteration results from a G to A substitution at nucleotide position 2353, causing the valine (V) at amino acid position 785 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0031	T;T;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.2	L;L;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.38	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.060	B;B;D;.
Vest4		0.10
MutPred		0.36		Gain of disorder (P = 0.0967);Gain of disorder (P = 0.0967);.;.;
MVP		0.57
MPC		0.14
ClinPred		0.090	T
GERP RS		5.7
Varity_R		0.053
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs758416659; hg19: chr10-99220723;