chr7-134575876-A-C

Position:

• chr7-134575876-A-C

Variant summary

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

The NM_001080538.3(AKR1B15):​c.692A>C​(p.Lys231Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,558 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AKR1B15 NM_001080538.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

Genes affected

AKR1B15 (HGNC:37281): (aldo-keto reductase family 1 member B15) Enables estradiol 17-beta-dehydrogenase activity. Predicted to be involved in estrogen biosynthetic process. Located in cytosol and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

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=0.36907893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1B15	NM_001080538.3	c.692A>C	p.Lys231Thr	missense_variant	8/12	ENST00000457545.7
AKR1B15	NM_001367820.1	c.692A>C	p.Lys231Thr	missense_variant	7/11
AKR1B15	NM_001367821.1	c.608A>C	p.Lys203Thr	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1B15	ENST00000457545.7	c.692A>C	p.Lys231Thr	missense_variant	8/12	5	NM_001080538.3
AKR1B15	ENST00000423958.2	c.692A>C	p.Lys231Thr	missense_variant	6/10	5
AKR1B15	ENST00000652743.1	c.608A>C	p.Lys203Thr	missense_variant	6/10			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461558 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727078

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Sep 25, 2023

The c.692A>C (p.K231T) alteration is located in exon 8 (coding exon 6) of the AKR1B15 gene. This alteration results from a A to C substitution at nucleotide position 692, causing the lysine (K) at amino acid position 231 to be replaced by a threonine (T). 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	0.28
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Benign	0.24
Sift	Uncertain	0.014	D;.
Sift4G	Uncertain	0.034	D;D
Vest4		0.34
MutPred		0.59		Loss of methylation at K231 (P = 0.0029);Loss of methylation at K231 (P = 0.0029);
MVP		0.23
MPC		0.31
ClinPred		0.99	D
GERP RS		2.7
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr7-134260628;