chr20-36935104-C-T

Variant names:

• chr20-36935104-C-T
• rs515726145
• NM_015474.4:c.434G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

The NM_015474.4(SAMHD1):​c.434G>A​(p.Arg145Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SAMHD1 NM_015474.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 6.15
• Publications: 12 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_015474.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-36935104-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 872202.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 20-36935104-C-T is Pathogenic according to our data. Variant chr20-36935104-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126412.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMHD1	NM_015474.4	MANE Select	c.434G>A	p.Arg145Gln	missense	Exon 4 of 16	NP_056289.2
	SAMHD1	NM_001363729.2		c.434G>A	p.Arg145Gln	missense	Exon 4 of 15	NP_001350658.1
	SAMHD1	NM_001363733.2		c.434G>A	p.Arg145Gln	missense	Exon 4 of 16	NP_001350662.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMHD1	ENST00000646673.2	MANE Select	c.434G>A	p.Arg145Gln	missense	Exon 4 of 16	ENSP00000493536.2
	SAMHD1	ENST00000262878.5	TSL:1	c.434G>A	p.Arg145Gln	missense	Exon 4 of 15	ENSP00000262878.5
	SAMHD1	ENST00000866371.1		c.434G>A	p.Arg145Gln	missense	Exon 4 of 17	ENSP00000536430.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251470 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: 0.00000684 AC: 10 AN: 1461748 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111886

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Aicardi-Goutieres syndrome 5 (2)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.93
Sift	Benign	0.042	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Loss of helix (P = 0.028)
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.85
gMVP		0.83
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs515726145; hg19: chr20-35563507; COSMIC: COSV99483854; COSMIC: COSV99483854;