6-146672393-A-G

Position:

• chr6-146672393-A-G

Variant summary

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

The NM_024694.4(ADGB):​c.1013A>G​(p.Asp338Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGB NM_024694.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

Genes affected

ADGB (HGNC:21212): (androglobin) Predicted to enable calcium-dependent cysteine-type endopeptidase activity; heme binding activity; and oxygen binding activity. Predicted to be involved in proteolysis. [provided by Alliance of Genome Resources, Apr 2022]

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=0.08569485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGB	NM_024694.4	c.1013A>G	p.Asp338Gly	missense_variant	8/36	ENST00000397944.8	NP_078970.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGB	ENST00000397944.8	c.1013A>G	p.Asp338Gly	missense_variant	8/36	5	NM_024694.4	ENSP00000381036	P4
ADGB	ENST00000493950.6	c.*123A>G		3_prime_UTR_variant, NMD_transcript_variant	6/32	1		ENSP00000430244
ADGB	ENST00000681847.1	c.1013A>G	p.Asp338Gly	missense_variant	8/36			ENSP00000505524	A2
ADGB	ENST00000326929.8	n.1054A>G		non_coding_transcript_exon_variant	8/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

May 28, 2024

The c.1013A>G (p.D338G) alteration is located in exon 8 (coding exon 8) of the ADGB gene. This alteration results from a A to G substitution at nucleotide position 1013, causing the aspartic acid (D) at amino acid position 338 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.62
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.053
Sift	Benign	0.47	T
Sift4G	Benign	0.21	T
Polyphen		0.41	B
Vest4		0.22
MutPred		0.36		Gain of sheet (P = 0.0221);
MVP		0.030
ClinPred		0.12	T
GERP RS		1.8
Varity_R		0.087
gMVP		0.18

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: rs1417050909; hg19: chr6-146993529;