10-97459389-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022362.5(MMS19):c.2877T>G(p.Phe959Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 6.9e-7 (0 hom.)
• Consequence: MMS19 NM_022362.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.854

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12882808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMS19	NM_022362.5	c.2877T>G	p.Phe959Leu	missense_variant	28/31	ENST00000438925.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMS19	ENST00000438925.7	c.2877T>G	p.Phe959Leu	missense_variant	28/31	1	NM_022362.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453000 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721972

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Jun 07, 2023

The c.2877T>G (p.F959L) alteration is located in exon 28 (coding exon 28) of the MMS19 gene. This alteration results from a T to G substitution at nucleotide position 2877, causing the phenylalanine (F) at amino acid position 959 to be replaced by a leucine (L). 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	0.60
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	11
Dann	Benign	0.84
DEOGEN2	Benign	0.0011	T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.2	N;N;.;.
MutationTaster	Benign	0.84	D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.81	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.85	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.31
MutPred		0.63		Loss of methylation at K958 (P = 0.0268);Loss of methylation at K958 (P = 0.0268);.;.;
MVP		0.22
MPC		0.16
ClinPred		0.097	T
GERP RS		-4.4
Varity_R		0.13
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-99219146;