NM_001628.4:c.429+6A>G

Variant names:

• chr7-134449714-T-C
• rs150113325
• NM_001628.4:c.429+6A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001628.4(AKR1B1):​c.429+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,613,394 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (61 hom.)
• Consequence: AKR1B1 NM_001628.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009719
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82
• Publications: 0 publications found

Genes affected

AKR1B1 (HGNC:381): (aldo-keto reductase family 1 member B) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. This member catalyzes the reduction of a number of aldehydes, including the aldehyde form of glucose, and is thereby implicated in the development of diabetic complications by catalyzing the reduction of glucose to sorbitol. Multiple pseudogenes have been identified for this gene. The nomenclature system used by the HUGO Gene Nomenclature Committee to define human aldo-keto reductase family members is known to differ from that used by the Mouse Genome Informatics database. [provided by RefSeq, Feb 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-134449714-T-C is Benign according to our data. Variant chr7-134449714-T-C is described in ClinVar as Benign. ClinVar VariationId is 770191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00474 (6925/1461142) while in subpopulation AMR AF = 0.0185 (827/44724). AF 95% confidence interval is 0.0174. There are 61 homozygotes in GnomAdExome4. There are 3426 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001628.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1B1	NM_001628.4	MANE Select	c.429+6A>G		splice_region intron	N/A	NP_001619.1	P15121
	AKR1B1	NM_001346142.1		c.-4+6A>G		splice_region intron	N/A	NP_001333071.1
	AKR1B1	NR_144376.2		n.467+6A>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1B1	ENST00000285930.9	TSL:1 MANE Select	c.429+6A>G		splice_region intron	N/A	ENSP00000285930.3	P15121
	AKR1B1	ENST00000467829.1	TSL:1	n.532A>G		non_coding_transcript_exon	Exon 4 of 4
	AKR1B1	ENST00000491741.5	TSL:1	n.532A>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.00578 AC: 879 AN: 152134 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00754

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0328

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00877 AC: 2206 AN: 251466 AF XY: 0.00814

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0211

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0305

Gnomad NFE exome AF: 0.00402

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.00474 AC: 6925 AN: 1461142 Hom.: 61 Cov.: 31 AF XY: 0.00471 AC XY: 3426 AN XY: 726952

African (AFR) AF: 0.000538 AC: 18 AN: 33468

American (AMR) AF: 0.0185 AC: 827 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 468 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00388 AC: 335 AN: 86248

European-Finnish (FIN) AF: 0.0303 AC: 1616 AN: 53416

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00300 AC: 3334 AN: 1111334

Other (OTH) AF: 0.00522 AC: 315 AN: 60356

GnomAD4 genome AF: 0.00580 AC: 883 AN: 152252 Hom.: 12 Cov.: 32 AF XY: 0.00668 AC XY: 497 AN XY: 74456

African (AFR) AF: 0.000818 AC: 34 AN: 41550

American (AMR) AF: 0.00772 AC: 118 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4828

European-Finnish (FIN) AF: 0.0328 AC: 348 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00419 AC: 285 AN: 68006

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00578 Hom.: 2

Bravo AF: 0.00397

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.9
DANN	Benign	0.57
PhyloP100		-1.8
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.0040
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: rs150113325; hg19: chr7-134134466;