chr11-60069635-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006138.5(MS4A3):ā€‹c.575T>Cā€‹(p.Ile192Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

MS4A3
NM_006138.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00200
Variant links:
Genes affected
MS4A3 (HGNC:7317): (membrane spanning 4-domains A3) This gene encodes a member of the membrane-spanning 4A gene family. Members of this protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This family member likely plays a role in signal transduction and may function as a subunit associated with receptor complexes. The gene encoding this protein is localized to 11q12, among a cluster of related family members. Alternative splicing may result in multiple transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.046597004).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MS4A3NM_006138.5 linkuse as main transcriptc.575T>C p.Ile192Thr missense_variant 6/7 ENST00000278865.8
MS4A3NM_001031809.2 linkuse as main transcriptc.437T>C p.Ile146Thr missense_variant 5/6
MS4A3NM_001031666.2 linkuse as main transcriptc.206T>C p.Ile69Thr missense_variant 4/5
MS4A3XM_011545363.4 linkuse as main transcriptc.395T>C p.Ile132Thr missense_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MS4A3ENST00000278865.8 linkuse as main transcriptc.575T>C p.Ile192Thr missense_variant 6/71 NM_006138.5 P1Q96HJ5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251388
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135850
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 SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461288
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726988
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2024The c.575T>C (p.I192T) alteration is located in exon 6 (coding exon 5) of the MS4A3 gene. This alteration results from a T to C substitution at nucleotide position 575, causing the isoleucine (I) at amino acid position 192 to be replaced by a threonine (T). 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
0.083
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.44
DANN
Benign
0.51
DEOGEN2
Benign
0.016
.;.;T;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.00069
N
LIST_S2
Benign
0.36
T;T;.;.
M_CAP
Benign
0.0021
T
MetaRNN
Benign
0.047
T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
-0.41
.;.;N;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
2.2
N;N;N;N
REVEL
Benign
0.027
Sift
Benign
0.19
T;T;T;T
Sift4G
Benign
0.49
T;T;T;T
Polyphen
0.0
.;B;B;B
Vest4
0.038
MutPred
0.27
.;.;Loss of stability (P = 0.0646);.;
MVP
0.040
MPC
0.015
ClinPred
0.053
T
GERP RS
-0.53
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.031
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs770173506; hg19: chr11-59837108; API