13-30921020-C-A

Position:

• chr13-30921020-C-A

Variant summary

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

The NM_032849.4(MEDAG):​c.395C>A​(p.Thr132Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T132T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MEDAG NM_032849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

Genes affected

MEDAG (HGNC:25926): (mesenteric estrogen dependent adipogenesis) Predicted to be involved in positive regulation of fat cell differentiation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TEX26-AS1 (HGNC:42784): (TEX26 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEDAG	NM_032849.4	c.395C>A	p.Thr132Lys	missense_variant	3/5	ENST00000380482.9
TEX26-AS1	NR_038287.1	n.1437+9781G>T		intron_variant, non_coding_transcript_variant
MEDAG	XM_017020801.2	c.-59C>A		5_prime_UTR_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEDAG	ENST00000380482.9	c.395C>A	p.Thr132Lys	missense_variant	3/5	1	NM_032849.4	P1
TEX26-AS1	ENST00000585870.6	n.1437+9781G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460734 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.395C>A (p.T132K) alteration is located in exon 3 (coding exon 3) of the MEDAG gene. This alteration results from a C to A substitution at nucleotide position 395, causing the threonine (T) at amino acid position 132 to be replaced by a lysine (K). 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0079	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.27
Sift	Benign	0.052	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.45		Loss of sheet (P = 0.0228);
MVP		0.42
MPC		0.62
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.63

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: rs138327988; hg19: chr13-31495157;