6-37646268-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_153487.4(MDGA1):c.2154G>C(p.Glu718Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,606,184 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (20 hom.)
• Consequence: MDGA1 NM_153487.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.62

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0096515715).
• BP6: Variant 6-37646268-C-G is Benign according to our data. Variant chr6-37646268-C-G is described in ClinVar as [Benign]. Clinvar id is 786087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00798 (1216/152316) while in subpopulation AFR AF= 0.0265 (1102/41562). AF 95% confidence interval is 0.0252. There are 18 homozygotes in gnomad4. There are 612 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDGA1	NM_153487.4	c.2154G>C	p.Glu718Asp	missense_variant	11/17	ENST00000434837.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDGA1	ENST00000434837.8	c.2154G>C	p.Glu718Asp	missense_variant	11/17	1	NM_153487.4	P1

Frequencies

GnomAD3 genomes AF: 0.00797 AC: 1213 AN: 152198 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00276 AC: 659 AN: 238402 Hom.: 3 AF XY: 0.00261 AC XY: 337 AN XY: 129036

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.000516

Gnomad SAS exome AF: 0.00557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00119 AC: 1731 AN: 1453868 Hom.: 20 Cov.: 31 AF XY: 0.00125 AC XY: 901 AN XY: 722104

Gnomad4 AFR exome AF: 0.0245

Gnomad4 AMR exome AF: 0.00267

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.000279

Gnomad4 SAS exome AF: 0.00525

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00798 AC: 1216 AN: 152316 Hom.: 18 Cov.: 32 AF XY: 0.00822 AC XY: 612 AN XY: 74488

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00237 Hom.: 2

Bravo AF: 0.00938

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0261 AC: 111

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00311 AC: 376

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.12
Sift	Uncertain	0.015	D;.;D
Sift4G	Uncertain	0.047	D;.;D
Polyphen		0.98	D;.;.
Vest4		0.89
MutPred		0.36		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.55
MPC		0.88
ClinPred		0.029	T
GERP RS		4.0
Varity_R		0.16
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs192113659; hg19: chr6-37614044;