rs60720055

Variant names:

• chr5-126592703-A-G
• rs60720055
• NM_001182.5:c.273T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001182.5(ALDH7A1):​c.273T>C​(p.Thr91Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,613,936 control chromosomes in the GnomAD database, including 1,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T91T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (491 hom., cov: 32)
  • Exomes 𝑓: 0.024 (871 hom.)
• Consequence: ALDH7A1 NM_001182.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0950
• Publications: 6 publications found

Genes affected

ALDH7A1 (HGNC:877): (aldehyde dehydrogenase 7 family member A1) The protein encoded by this gene is a member of subfamily 7 in the aldehyde dehydrogenase gene family. These enzymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This particular member has homology to a previously described protein from the green garden pea, the 26g pea turgor protein. It is also involved in lysine catabolism that is known to occur in the mitochondrial matrix. Recent reports show that this protein is found both in the cytosol and the mitochondria, and the two forms likely arise from the use of alternative translation initiation sites. An additional variant encoding a different isoform has also been found for this gene. Mutations in this gene are associated with pyridoxine-dependent epilepsy. Several related pseudogenes have also been identified. [provided by RefSeq, Jan 2011]

ALDH7A1 Gene-Disease associations (from GenCC):

• pyridoxine-dependent epilepsy

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina, ClinGen
• pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 5-126592703-A-G is Benign according to our data. Variant chr5-126592703-A-G is described in ClinVar as Benign. ClinVar VariationId is 128347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.095 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001182.5. 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
	ALDH7A1	NM_001182.5	MANE Select	c.273T>C	p.Thr91Thr	synonymous	Exon 3 of 18	NP_001173.2	P49419-1
	ALDH7A1	NM_001201377.2		c.189T>C	p.Thr63Thr	synonymous	Exon 3 of 18	NP_001188306.1	P49419-2
	ALDH7A1	NM_001202404.2		c.273T>C	p.Thr91Thr	synonymous	Exon 3 of 16	NP_001189333.2	P49419-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	ENST00000409134.8	TSL:1 MANE Select	c.273T>C	p.Thr91Thr	synonymous	Exon 3 of 18	ENSP00000387123.3	P49419-1
	ALDH7A1	ENST00000636879.1	TSL:5	c.273T>C	p.Thr91Thr	synonymous	Exon 3 of 19	ENSP00000490811.1	A0A1B0GW77
	ALDH7A1	ENST00000939100.1		c.273T>C	p.Thr91Thr	synonymous	Exon 3 of 19	ENSP00000609159.1

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 8897 AN: 152168 Hom.: 491 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.0556

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0502

GnomAD2 exomes AF: 0.0303 AC: 7606 AN: 251410 AF XY: 0.0283

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.0226

Gnomad ASJ exome AF: 0.0597

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.0218

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0244 AC: 35628 AN: 1461650 Hom.: 871 Cov.: 30 AF XY: 0.0244 AC XY: 17750 AN XY: 727132

African (AFR) AF: 0.150 AC: 5028 AN: 33456

American (AMR) AF: 0.0249 AC: 1115 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0609 AC: 1591 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.0284 AC: 2446 AN: 86252

European-Finnish (FIN) AF: 0.00972 AC: 519 AN: 53398

Middle Eastern (MID) AF: 0.0371 AC: 213 AN: 5736

European-Non Finnish (NFE) AF: 0.0205 AC: 22761 AN: 1111880

Other (OTH) AF: 0.0323 AC: 1952 AN: 60380

GnomAD4 genome AF: 0.0585 AC: 8916 AN: 152286 Hom.: 491 Cov.: 32 AF XY: 0.0563 AC XY: 4195 AN XY: 74458

African (AFR) AF: 0.148 AC: 6128 AN: 41542

American (AMR) AF: 0.0414 AC: 633 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 193 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4830

European-Finnish (FIN) AF: 0.00819 AC: 87 AN: 10622

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0230 AC: 1568 AN: 68030

Other (OTH) AF: 0.0497 AC: 105 AN: 2114

Alfa AF: 0.0433 Hom.: 204

Bravo AF: 0.0650

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0236

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	4	Pyridoxine-dependent epilepsy (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.6
DANN	Benign	0.71
PhyloP100		-0.095
Mutation Taster		=98/2	polymorphism (auto)

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: rs60720055; hg19: chr5-125928395;