20-36897960-C-G

Variant names:

• chr20-36897960-C-G
• rs515726143
• NM_015474.4:c.1609-1G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_015474.4(SAMHD1):​c.1609-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SAMHD1 NM_015474.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.16
• Publications: 5 publications found

Genes affected

SAMHD1 (HGNC:15925): (SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1) This gene may play a role in regulation of the innate immune response. The encoded protein is upregulated in response to viral infection and may be involved in mediation of tumor necrosis factor-alpha proinflammatory responses. Mutations in this gene have been associated with Aicardi-Goutieres syndrome. [provided by RefSeq, Mar 2010]

SAMHD1 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• SAMHD1-related type 1 interferonopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Moyamoya disease

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial chilblain lupus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• chilblain lupus 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• chilblain lupus

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.073365234 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.4, offset of 19, new splice context is: cgtttcacaacttctgccAGaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-36897960-C-G is Pathogenic according to our data. Variant chr20-36897960-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 126409.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015474.4. 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
	SAMHD1	NM_015474.4	MANE Select	c.1609-1G>C		splice_acceptor intron	N/A	NP_056289.2
	SAMHD1	NM_001363729.2		c.1504-1G>C		splice_acceptor intron	N/A	NP_001350658.1	Q9Y3Z3-4
	SAMHD1	NM_001363733.2		c.1609-1G>C		splice_acceptor intron	N/A	NP_001350662.1	A0A2R8YCS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMHD1	ENST00000646673.2	MANE Select	c.1609-1G>C		splice_acceptor intron	N/A	ENSP00000493536.2	Q9Y3Z3-1
	SAMHD1	ENST00000262878.5	TSL:1	c.1504-1G>C		splice_acceptor intron	N/A	ENSP00000262878.5	Q9Y3Z3-4
	SAMHD1	ENST00000866371.1		c.1747-1G>C		splice_acceptor intron	N/A	ENSP00000536430.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251328 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Aicardi-Goutieres syndrome 5 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.2
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.94		Position offset: -1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs515726143;

hg19: chr20-35526363;