rs74882337

chr7-122093136-G-Achr7-122093136-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005763.4(AASS):c.1678C>T(p.Pro560Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,613,710 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (37 hom.)
• Consequence: AASS NM_005763.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 7.69

Genes affected

AASS (HGNC:17366): (aminoadipate-semialdehyde synthase) This gene encodes a bifunctional enzyme that catalyzes the first two steps in the mammalian lysine degradation pathway. The N-terminal and the C-terminal portions of this enzyme contain lysine-ketoglutarate reductase and saccharopine dehydrogenase activity, respectively, resulting in the conversion of lysine to alpha-aminoadipic semialdehyde. Mutations in this gene are associated with familial hyperlysinemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 7-122093136-G-A is Benign according to our data. Variant chr7-122093136-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-122093136-G-A is described in Lovd as [Likely_benign]. Variant chr7-122093136-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00449 (683/152236) while in subpopulation NFE AF= 0.00785 (534/68022). AF 95% confidence interval is 0.0073. There are 3 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AASS	NM_005763.4	c.1678C>T	p.Pro560Ser	missense_variant	16/24	ENST00000417368.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AASS	ENST00000417368.7	c.1678C>T	p.Pro560Ser	missense_variant	16/24	1	NM_005763.4	P1

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 683 AN: 152118 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00384 AC: 964 AN: 250956 Hom.: 5 AF XY: 0.00364 AC XY: 493 AN XY: 135606

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00690

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00623 AC: 9098 AN: 1461474 Hom.: 37 Cov.: 32 AF XY: 0.00599 AC XY: 4355 AN XY: 727060

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00316

Gnomad4 NFE exome AF: 0.00759

Gnomad4 OTH exome AF: 0.00396

GnomAD4 genome AF: 0.00449 AC: 683 AN: 152236 Hom.: 3 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74440

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00785

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00638 Hom.: 10

Bravo AF: 0.00448

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00390 AC: 473

EpiCase AF: 0.00562

EpiControl AF: 0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	AASS: BS2 -

AASS-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hyperlysinemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.22
Sift	Benign	0.74	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.95	P;P
Vest4		0.68
MVP		0.72
MPC		0.63
ClinPred		0.026	T
GERP RS		6.0
Varity_R		0.26
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74882337; hg19: chr7-121733190;