20-34259961-A-G

Variant names:

• chr20-34259961-A-G
• rs819135
• NM_001672.3:c.-10-404A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001672.3(ASIP):​c.-10-404A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 151,592 control chromosomes in the GnomAD database, including 28,439 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (28439 hom., cov: 29)
• Consequence: ASIP NM_001672.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.953
• Publications: 5 publications found

Genes affected

ASIP (HGNC:745): (agouti signaling protein) In mice, the agouti gene encodes a paracrine signaling molecule that causes hair follicle melanocytes to synthesize pheomelanin, a yellow pigment, instead of the black or brown pigment, eumelanin. Pleiotropic effects of constitutive expression of the mouse gene include adult-onset obesity, increased tumor susceptibility, and premature infertility. This gene is highly similar to the mouse gene and encodes a secreted protein that may (1) affect the quality of hair pigmentation, (2) act as a pharmacological antagonist of alpha-melanocyte-stimulating hormone, (3) play a role in neuroendocrine aspects of melanocortin action, and (4) have a functional role in regulating lipid metabolism in adipocytes. [provided by RefSeq, Jul 2008]

ENSG00000250917 (HGNC:):

AHCY (HGNC:343): (adenosylhomocysteinase) S-adenosylhomocysteine hydrolase belongs to the adenosylhomocysteinase family. It catalyzes the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) to adenosine (Ado) and L-homocysteine (Hcy). Thus, it regulates the intracellular S-adenosylhomocysteine (SAH) concentration thought to be important for transmethylation reactions. Deficiency in this protein is one of the different causes of hypermethioninemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

AHCY Gene-Disease associations (from GenCC):

• hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.882 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001672.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASIP	NM_001672.3	MANE Select	c.-10-404A>G		intron	N/A	NP_001663.2
	ASIP	NM_001385218.1		c.-10-404A>G		intron	N/A	NP_001372147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASIP	ENST00000374954.4	TSL:1 MANE Select	c.-10-404A>G		intron	N/A	ENSP00000364092.3
	ASIP	ENST00000568305.5	TSL:5	c.-10-404A>G		intron	N/A	ENSP00000454804.1
	ENSG00000250917	ENST00000512005.1	TSL:3	n.148-9823T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.579 AC: 87668 AN: 151474 Hom.: 28375 Cov.: 29

Gnomad AFR AF: 0.889

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.563

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.579 AC: 87788 AN: 151592 Hom.: 28439 Cov.: 29 AF XY: 0.575 AC XY: 42571 AN XY: 74052

African (AFR) AF: 0.890 AC: 36810 AN: 41372

American (AMR) AF: 0.536 AC: 8142 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1794 AN: 3470

East Asian (EAS) AF: 0.627 AC: 3211 AN: 5122

South Asian (SAS) AF: 0.396 AC: 1896 AN: 4788

European-Finnish (FIN) AF: 0.412 AC: 4316 AN: 10488

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29730 AN: 67854

Other (OTH) AF: 0.562 AC: 1181 AN: 2100

Alfa AF: 0.559 Hom.: 3625

Bravo AF: 0.603

Asia WGS AF: 0.525 AC: 1826 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.75
DANN	Benign	0.83
PhyloP100		-0.95
Mutation Taster		=100/0	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: rs819135; hg19: chr20-32847767;