chr7-138076601-A-T

Variant names:

• chr7-138076601-A-T
• rs769791635
• NM_005989.4:c.83A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005989.4(AKR1D1):​c.83A>T​(p.Glu28Val) 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. 16/22 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: AKR1D1 NM_005989.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70
• Publications: 0 publications found

Genes affected

AKR1D1 (HGNC:388): (aldo-keto reductase family 1 member D1) The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet. [provided by RefSeq, Jul 2010]

AKR1D1 Gene-Disease associations (from GenCC):

• congenital bile acid synthesis defect 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.17215 (below the threshold of 3.09). Trascript score misZ: 0.98686 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital bile acid synthesis defect 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.091190845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1D1	NM_005989.4	c.83A>T	p.Glu28Val	missense_variant	Exon 1 of 9	ENST00000242375.8	NP_005980.1
AKR1D1	NM_001190907.2	c.83A>T	p.Glu28Val	missense_variant	Exon 1 of 8		NP_001177836.1
AKR1D1	NM_001190906.2	c.83A>T	p.Glu28Val	missense_variant	Exon 1 of 8		NP_001177835.1
AKR1D1	XM_047420763.1	c.83A>T	p.Glu28Val	missense_variant	Exon 1 of 8		XP_047276719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1D1	ENST00000242375.8	c.83A>T	p.Glu28Val	missense_variant	Exon 1 of 9	1	NM_005989.4	ENSP00000242375.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83A>T (p.E28V) alteration is located in exon 1 (coding exon 1) of the AKR1D1 gene. This alteration results from a A to T substitution at nucleotide position 83, causing the glutamic acid (E) at amino acid position 28 to be replaced by a valine (V). 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	0.21
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.072	.;.;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.091	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.44	N;N;N;.
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.36	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.0020	.;.;B;.
Vest4		0.38
MutPred		0.49		Loss of disorder (P = 0.0222);Loss of disorder (P = 0.0222);Loss of disorder (P = 0.0222);Loss of disorder (P = 0.0222);
MVP		0.49
MPC		0.14
ClinPred		0.11	T
GERP RS		4.9
PromoterAI		-0.077	Neutral
Varity_R		0.43
gMVP		0.81
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs769791635; hg19: chr7-137761347;