6-37638228-C-A

Variant names:

• chr6-37638228-C-A
• rs201447768
• NM_153487.4:c.2753G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153487.4(MDGA1):​c.2753G>T​(p.Arg918Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R918Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MDGA1 NM_153487.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.52
• Publications: 0 publications found

Genes affected

MDGA1 (HGNC:19267): (MAM domain containing glycosylphosphatidylinositol anchor 1) This gene encodes a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein that is expressed predominantly in the developing nervous system. In addition to possessing several cell adhesion molecule-like domains, the mature protein has six Ig-like domains, a single fibronectin type III domain, a MAM domain and a C-terminal GPI-anchoring site. Studies in other mammals suggest this protein plays a role in cell adhesion, migration, and axon guidance and, in the developing brain, neuronal migration. In humans, this gene is associated with bipolar disorder and schizophrenia. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30106458).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153487.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDGA1	NM_153487.4	MANE Select	c.2753G>T	p.Arg918Leu	missense	Exon 16 of 17	NP_705691.1	Q8NFP4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDGA1	ENST00000434837.8	TSL:1 MANE Select	c.2753G>T	p.Arg918Leu	missense	Exon 16 of 17	ENSP00000402584.2	Q8NFP4-1
	MDGA1	ENST00000505425.5	TSL:5	c.2753G>T	p.Arg918Leu	missense	Exon 16 of 16	ENSP00000422042.1	Q8NFP4-2
	MDGA1	ENST00000650466.1		c.2753G>T	p.Arg918Leu	missense	Exon 16 of 18	ENSP00000498018.1	A0A3B3IU48

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461544 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727082

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.15
Sift	Benign	0.046	D
Sift4G	Uncertain	0.026	D
Polyphen		0.92	P
Vest4		0.76
MutPred		0.58		Loss of phosphorylation at T921 (P = 0.0468)
MVP		0.35
MPC		1.1
ClinPred		0.91	D
GERP RS		3.9
Varity_R		0.15
gMVP		0.50
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201447768; hg19: chr6-37606004;