20-34269192-A-G

Variant names:

• chr20-34269192-A-G
• rs6058017
• NM_001672.3:c.*25A>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.*25A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,476,164 control chromosomes in the GnomAD database, including 26,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.28 (10483 hom., cov: 32)
  • Exomes 𝑓: 0.13 (16483 hom.)
• Consequence: ASIP NM_001672.3 3_prime_UTR
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.372
• Publications: 44 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 = 0.662 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.*25A>G		3_prime_UTR	Exon 4 of 4	NP_001663.2
	ASIP	NM_001385218.1		c.*25A>G		3_prime_UTR	Exon 4 of 4	NP_001372147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASIP	ENST00000374954.4	TSL:1 MANE Select	c.*25A>G		3_prime_UTR	Exon 4 of 4	ENSP00000364092.3
	ENSG00000250917	ENST00000512005.1	TSL:3	n.147+11835T>C		intron	N/A
	ASIP	ENST00000568305.5	TSL:5	c.*25A>G		downstream_gene	N/A	ENSP00000454804.1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42442 AN: 152056 Hom.: 10463 Cov.: 32

Gnomad AFR AF: 0.669

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.151 AC: 13215 AN: 87524 AF XY: 0.155

Gnomad AFR exome AF: 0.659

Gnomad AMR exome AF: 0.0848

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.216

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.129 AC: 170694 AN: 1323992 Hom.: 16483 Cov.: 32 AF XY: 0.130 AC XY: 84116 AN XY: 645926

African (AFR) AF: 0.697 AC: 18984 AN: 27254

American (AMR) AF: 0.0963 AC: 2683 AN: 27868

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 3539 AN: 21400

East Asian (EAS) AF: 0.167 AC: 5524 AN: 33028

South Asian (SAS) AF: 0.210 AC: 14694 AN: 69834

European-Finnish (FIN) AF: 0.122 AC: 4886 AN: 39992

Middle Eastern (MID) AF: 0.221 AC: 900 AN: 4072

European-Non Finnish (NFE) AF: 0.105 AC: 110011 AN: 1045698

Other (OTH) AF: 0.173 AC: 9473 AN: 54846

GnomAD4 genome AF: 0.279 AC: 42493 AN: 152172 Hom.: 10483 Cov.: 32 AF XY: 0.276 AC XY: 20564 AN XY: 74416

African (AFR) AF: 0.669 AC: 27756 AN: 41494

American (AMR) AF: 0.150 AC: 2301 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 640 AN: 3472

East Asian (EAS) AF: 0.216 AC: 1115 AN: 5170

South Asian (SAS) AF: 0.206 AC: 994 AN: 4828

European-Finnish (FIN) AF: 0.123 AC: 1303 AN: 10606

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7718 AN: 67986

Other (OTH) AF: 0.238 AC: 504 AN: 2114

Alfa AF: 0.221 Hom.: 1476

Bravo AF: 0.296

Asia WGS AF: 0.220 AC: 767 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

SKIN/HAIR/EYE PIGMENTATION 9, DARK/LIGHT HAIR Other:1

Jul 26, 2018

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.4
DANN	Benign	0.27
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6058017; hg19: chr20-32856998;