Genetic Variant NM_148975.3:c.295G>T (chr11-60297290-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_148975.3(MS4A4A):c.295G>T(p.Val99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V99M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MS4A4A
NM_148975.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.156

Publications

0 publications found

Variant links:

Genes affected

MS4A4A (HGNC:13371): (membrane spanning 4-domains A4A) This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features, similar intron/exon splice boundaries, and display unique expression patterns in hematopoietic cells and nonlymphoid tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

MS4A4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16672951).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148975.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MS4A4A	NM_148975.3	MANE Select	c.295G>T	p.Val99Leu	missense	Exon 3 of 7	NP_683876.1	Q96JQ5-1
MS4A4A	NM_024021.4		c.238G>T	p.Val80Leu	missense	Exon 4 of 8	NP_076926.2
MS4A4A	NM_001243266.2		c.295G>T	p.Val99Leu	missense	Exon 3 of 6	NP_001230195.1	Q96JQ5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MS4A4A	ENST00000337908.5	TSL:1 MANE Select	c.295G>T	p.Val99Leu	missense	Exon 3 of 7	ENSP00000338648.4	Q96JQ5-1
MS4A4A	ENST00000649552.2		c.313G>T	p.Val105Leu	missense	Exon 4 of 8	ENSP00000497952.2	A0A3B3ITV6
MS4A4A	ENST00000679553.1		c.313G>T	p.Val105Leu	missense	Exon 3 of 7	ENSP00000505712.1	A0A7P0T9I4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111392

Other (OTH)

AF:

0.00

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Benign

0.33

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.3

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0063

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.60

M_CAP

Benign

0.0030

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.91

PhyloP100

0.16

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

REVEL

Benign

0.090

Sift

Benign

0.28

Sift4G

Benign

0.28

Polyphen

0.91

Vest4

0.26

MutPred

0.50

Gain of glycosylation at S98 (P = 0.1401)

MVP

0.055

MPC

0.19

ClinPred

0.66

GERP RS

-0.63

Varity_R

0.20

gMVP

0.10

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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