chr6-37638288-G-A

Variant names:

• chr6-37638288-G-A
• rs371103978
• NM_153487.4:c.2693C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153487.4(MDGA1):​c.2693C>T​(p.Pro898Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,611,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MDGA1 NM_153487.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26871356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDGA1	NM_153487.4	c.2693C>T	p.Pro898Leu	missense_variant	Exon 16 of 17	ENST00000434837.8	NP_705691.1
MDGA1	XM_006715056.4	c.2693C>T	p.Pro898Leu	missense_variant	Exon 16 of 16		XP_006715119.1
MDGA1	XM_017010734.2	c.2693C>T	p.Pro898Leu	missense_variant	Exon 16 of 17		XP_016866223.1
MDGA1	XM_047418637.1	c.2525C>T	p.Pro842Leu	missense_variant	Exon 16 of 16		XP_047274593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDGA1	ENST00000434837.8	c.2693C>T	p.Pro898Leu	missense_variant	Exon 16 of 17	1	NM_153487.4	ENSP00000402584.2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151952 Hom.: 0 Cov.: 32

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: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000323 AC: 8 AN: 247318 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 134114

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459550 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725880

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151952 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74200

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: 0.0000945

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000497 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2693C>T (p.P898L) alteration is located in exon 16 (coding exon 16) of the MDGA1 gene. This alteration results from a C to T substitution at nucleotide position 2693, causing the proline (P) at amino acid position 898 to be replaced by a leucine (L). 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	0.084
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.51
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0061
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.49	N;.;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.091
Sift	Benign	0.061	T;.;D
Sift4G	Uncertain	0.045	D;.;D
Polyphen		0.13	B;.;B
Vest4		0.22
MVP		0.17
MPC		0.28
ClinPred		0.15	T
GERP RS		3.9
Varity_R		0.059
gMVP		0.33

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: rs371103978; hg19: chr6-37606064;