11-60335034-G-C

Variant names:

• chr11-60335034-G-C
• rs2304933
• NM_139249.4:c.139G>C

Variant summary

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

The NM_139249.4(MS4A6E):​c.139G>C​(p.Val47Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,880 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. 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. V47F) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: MS4A6E NM_139249.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164

Genes affected

MS4A6E (HGNC:14285): (membrane spanning 4-domains A6E) This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent 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. The gene encoding this protein is localized to 11q12.3, among a cluster of family members. [provided by RefSeq, Jul 2008]

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=0.11607653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MS4A6E	NM_139249.4	c.139G>C	p.Val47Leu	missense_variant	Exon 2 of 5	ENST00000684409.1	NP_640342.1
MS4A6E	NR_170614.1	n.307G>C		non_coding_transcript_exon_variant	Exon 2 of 6
MS4A6E	NR_170615.1	n.307G>C		non_coding_transcript_exon_variant	Exon 2 of 5
MS4A6E	NR_170616.1	n.307G>C		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MS4A6E	ENST00000684409.1	c.139G>C	p.Val47Leu	missense_variant	Exon 2 of 5		NM_139249.4	ENSP00000507799.1
MS4A6E	ENST00000300182.8	c.139G>C	p.Val47Leu	missense_variant	Exon 1 of 4	1		ENSP00000300182.4
MS4A6E	ENST00000530509.1	n.58G>C		non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000436675.1
MS4A6E	ENST00000532756.1	n.64G>C		non_coding_transcript_exon_variant	Exon 1 of 5	4		ENSP00000432963.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251242 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135794

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 38

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74152

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.2
DANN	Benign	0.89
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.053
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.028	D
Polyphen		0.91	P
Vest4		0.12
MutPred		0.36		Gain of helix (P = 0.0143);
MVP		0.10
MPC		0.035
ClinPred		0.36	T
GERP RS		2.2
Varity_R		0.13
gMVP		0.35

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: rs2304933; hg19: chr11-60102507;