7-66092577-C-T

Variant names:

• chr7-66092577-C-T
• rs75300185
• NM_000048.4:c.1164C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000048.4(ASL):​c.1164C>T​(p.His388His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,610,882 control chromosomes in the GnomAD database, including 499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (60 hom., cov: 32)
  • Exomes 𝑓: 0.010 (439 hom.)
• Consequence: ASL NM_000048.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.46
• Publications: 6 publications found

Genes affected

ASL (HGNC:746): (argininosuccinate lyase) This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ASL Gene-Disease associations (from GenCC):

• argininosuccinic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000249319 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 7-66092577-C-T is Benign according to our data. Variant chr7-66092577-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000048.4. 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
	ASL	NM_000048.4	MANE Select	c.1164C>T	p.His388His	synonymous	Exon 16 of 17	NP_000039.2
	ASL	NM_001024943.2		c.1164C>T	p.His388His	synonymous	Exon 15 of 16	NP_001020114.1
	ASL	NM_001024944.2		c.1104C>T	p.His368His	synonymous	Exon 14 of 15	NP_001020115.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	ENST00000304874.14	TSL:1 MANE Select	c.1164C>T	p.His388His	synonymous	Exon 16 of 17	ENSP00000307188.9
	ASL	ENST00000395332.8	TSL:1	c.1164C>T	p.His388His	synonymous	Exon 15 of 16	ENSP00000378741.3
	ENSG00000249319	ENST00000450043.2	TSL:5	c.477C>T	p.His159His	synonymous	Exon 7 of 12	ENSP00000396527.2

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2264 AN: 152116 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0914

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0218 AC: 5427 AN: 248716 AF XY: 0.0199

Gnomad AFR exome AF: 0.00292

Gnomad AMR exome AF: 0.0399

Gnomad ASJ exome AF: 0.00587

Gnomad EAS exome AF: 0.0872

Gnomad FIN exome AF: 0.0674

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0105 AC: 15262 AN: 1458652 Hom.: 439 Cov.: 32 AF XY: 0.0102 AC XY: 7406 AN XY: 725764

African (AFR) AF: 0.00439 AC: 147 AN: 33468

American (AMR) AF: 0.0377 AC: 1684 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 159 AN: 26136

East Asian (EAS) AF: 0.105 AC: 4149 AN: 39698

South Asian (SAS) AF: 0.00583 AC: 503 AN: 86232

European-Finnish (FIN) AF: 0.0688 AC: 3486 AN: 50660

Middle Eastern (MID) AF: 0.00899 AC: 49 AN: 5448

European-Non Finnish (NFE) AF: 0.00368 AC: 4093 AN: 1111960

Other (OTH) AF: 0.0164 AC: 992 AN: 60326

GnomAD4 genome AF: 0.0149 AC: 2274 AN: 152230 Hom.: 60 Cov.: 32 AF XY: 0.0179 AC XY: 1329 AN XY: 74404

African (AFR) AF: 0.00330 AC: 137 AN: 41568

American (AMR) AF: 0.0242 AC: 369 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.0914 AC: 471 AN: 5154

South Asian (SAS) AF: 0.00830 AC: 40 AN: 4822

European-Finnish (FIN) AF: 0.0752 AC: 798 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00566 AC: 385 AN: 68024

Other (OTH) AF: 0.0237 AC: 50 AN: 2108

Alfa AF: 0.00797 Hom.: 11

Bravo AF: 0.0112

Asia WGS AF: 0.0720 AC: 249 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Argininosuccinate lyase deficiency (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.8
DANN	Benign	0.70
PhyloP100		-3.5
Mutation Taster		=94/6	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: rs75300185; hg19: chr7-65557564;