chr9-114060987-C-T

Position:

• chr9-114060987-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000265132.8(AMBP):​c.965G>A​(p.Gly322Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AMBP ENST00000265132.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71

Genes affected

AMBP (HGNC:453): (alpha-1-microglobulin/bikunin precursor) This gene encodes a complex glycoprotein secreted in plasma. The precursor is proteolytically processed into distinct functioning proteins: alpha-1-microglobulin, which belongs to the superfamily of lipocalin transport proteins and may play a role in the regulation of inflammatory processes, and bikunin, which is a urinary trypsin inhibitor belonging to the superfamily of Kunitz-type protease inhibitors and plays an important role in many physiological and pathological processes. This gene is located on chromosome 9 in a cluster of lipocalin genes. [provided by RefSeq, Jul 2008]

AMBP (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMBP	NM_001633.4	c.965G>A	p.Gly322Asp	missense_variant	9/10	ENST00000265132.8	NP_001624.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMBP	ENST00000265132.8	c.965G>A	p.Gly322Asp	missense_variant	9/10	1	NM_001633.4	ENSP00000265132.3
AMBP	ENST00000540645.5	n.1279G>A		non_coding_transcript_exon_variant	8/8	2
AMBP	ENST00000466610.6	c.*5G>A		downstream_gene_variant		3		ENSP00000475149.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Oct 17, 2023

The c.965G>A (p.G322D) alteration is located in exon 9 (coding exon 9) of the AMBP gene. This alteration results from a G to A substitution at nucleotide position 965, causing the glycine (G) at amino acid position 322 to be replaced by an aspartic acid (D). 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	0.89
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.95		Gain of relative solvent accessibility (P = 0.09);
MVP		0.89
MPC		0.54
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-116823267;