Genetic Variant NM_001350599.2:c.3672G>C (chr6-97146866-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001350599.2(MMS22L):c.3672G>C(p.Leu1224Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,403,318 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MMS22L
NM_001350599.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.01

Publications

0 publications found

Variant links:

Genes affected

MMS22L (HGNC:21475): (MMS22 like, DNA repair protein) The protein encoded by this gene forms a complex with tonsoku-like, DNA repair protein (TONSL), and this complex recognizes and repairs DNA double-strand breaks at sites of stalled or collapsed replication forks. The encoded protein also can bind with the histone-associated protein NFKBIL2 to help regulate the chromatin state at stalled replication forks. Finally, this gene appears to be overexpressed in most lung and esophageal cancers. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

MMS22L links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350599.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMS22L	NM_001350599.2	MANE Select	c.3672G>C	p.Leu1224Phe	missense	Exon 25 of 25	NP_001337528.1	Q6ZRQ5
MMS22L	NM_198468.4		c.3672G>C	p.Leu1224Phe	missense	Exon 25 of 25	NP_940870.2	Q6ZRQ5
MMS22L	NM_001350600.2		c.2823G>C	p.Leu941Phe	missense	Exon 24 of 24	NP_001337529.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMS22L	ENST00000683635.1	MANE Select	c.3672G>C	p.Leu1224Phe	missense	Exon 25 of 25	ENSP00000508046.1	Q6ZRQ5
MMS22L	ENST00000275053.8	TSL:2	c.3672G>C	p.Leu1224Phe	missense	Exon 25 of 25	ENSP00000275053.4	Q6ZRQ5
MMS22L	ENST00000929352.1		c.3672G>C	p.Leu1224Phe	missense	Exon 25 of 25	ENSP00000599411.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1403318

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697872

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28704

American (AMR)

AF:

0.00

AC:

AN:

29116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24128

East Asian (EAS)

AF:

0.00

AC:

AN:

36018

South Asian (SAS)

AF:

0.00

AC:

AN:

76614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5604

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1092434

Other (OTH)

AF:

0.00

AC:

AN:

57856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.8

PhyloP100

1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.1

REVEL

Benign

0.21

Sift

Benign

0.047

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.55

MutPred

0.27

Loss of disorder (P = 0.0784)

MVP

0.15

MPC

0.38

ClinPred

0.98

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.32

Mutation Taster

=86/14

polymorphism

(source)

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over