20-34254551-T-G

Variant names:

• chr20-34254551-T-G
• rs819163
• NM_001672.3:c.-10-5814T>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.-10-5814T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 152,154 control chromosomes in the GnomAD database, including 1,394 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 0.13 (1394 hom., cov: 32)
• Consequence: ASIP NM_001672.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300
• Publications: 8 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASIP	NM_001672.3	c.-10-5814T>G		intron_variant	Intron 1 of 3	ENST00000374954.4	NP_001663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASIP	ENST00000374954.4	c.-10-5814T>G		intron_variant	Intron 1 of 3	1	NM_001672.3	ENSP00000364092.3
ASIP	ENST00000568305.5	c.-10-5814T>G		intron_variant	Intron 1 of 3	5		ENSP00000454804.1
ENSG00000250917	ENST00000512005.1	n.148-4413A>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19868 AN: 152036 Hom.: 1390 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.136

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

GnomAD4 genome AF: 0.131 AC: 19887 AN: 152154 Hom.: 1394 Cov.: 32 AF XY: 0.132 AC XY: 9850 AN XY: 74376

African (AFR) AF: 0.156 AC: 6456 AN: 41502

American (AMR) AF: 0.0878 AC: 1344 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 625 AN: 3470

East Asian (EAS) AF: 0.216 AC: 1115 AN: 5168

South Asian (SAS) AF: 0.203 AC: 979 AN: 4816

European-Finnish (FIN) AF: 0.123 AC: 1303 AN: 10594

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.112 AC: 7627 AN: 67992

Other (OTH) AF: 0.136 AC: 287 AN: 2110

Alfa AF: 0.118 Hom.: 1141

Bravo AF: 0.127

Asia WGS AF: 0.189 AC: 655 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.63
PhyloP100		-0.0030
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: rs819163; hg19: chr20-32842357;