rs41270237

Variant names:

• chr2-190986920-C-T
• rs41270237
• NM_007315.4:c.1155G>A
• STAT1 p.Thr385Thr

Your query was ambiguous. Multiple possible variants found:

• chr2-190986920-C-T
• chr2-190986920-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007315.4(STAT1):​c.1155G>A​(p.Thr385Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,614,156 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (27 hom.)
• Consequence: STAT1 NM_007315.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.709
• Publications: 5 publications found

Genes affected

STAT1 (HGNC:11362): (signal transducer and activator of transcription 1) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]

STAT1 Gene-Disease associations (from GenCC):

• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
• immunodeficiency 31B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-190986920-C-T is Benign according to our data. Variant chr2-190986920-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 333279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.709 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00286 (436/152278) while in subpopulation SAS AF = 0.00518 (25/4826). AF 95% confidence interval is 0.0036. There are 1 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 27 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007315.4. 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
	STAT1	NM_007315.4	MANE Select	c.1155G>A	p.Thr385Thr	synonymous	Exon 14 of 25	NP_009330.1	P42224-1
	STAT1	NM_001384891.1		c.1191G>A	p.Thr397Thr	synonymous	Exon 14 of 25	NP_001371820.1
	STAT1	NM_001384886.1		c.1155G>A	p.Thr385Thr	synonymous	Exon 14 of 25	NP_001371815.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT1	ENST00000361099.8	TSL:1 MANE Select	c.1155G>A	p.Thr385Thr	synonymous	Exon 14 of 25	ENSP00000354394.4	P42224-1
	STAT1	ENST00000409465.5	TSL:1	c.1155G>A	p.Thr385Thr	synonymous	Exon 13 of 24	ENSP00000386244.1	P42224-1
	STAT1	ENST00000392322.7	TSL:1	c.1155G>A	p.Thr385Thr	synonymous	Exon 14 of 23	ENSP00000376136.3	P42224-2

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00416 AC: 1046 AN: 251400 AF XY: 0.00446

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00377 AC: 5507 AN: 1461878 Hom.: 27 Cov.: 32 AF XY: 0.00382 AC XY: 2779 AN XY: 727242

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00279 AC: 125 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 622 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00636 AC: 549 AN: 86258

European-Finnish (FIN) AF: 0.00348 AC: 186 AN: 53418

Middle Eastern (MID) AF: 0.0199 AC: 115 AN: 5768

European-Non Finnish (NFE) AF: 0.00323 AC: 3592 AN: 1111998

Other (OTH) AF: 0.00493 AC: 298 AN: 60396

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00283 AC XY: 211 AN XY: 74462

African (AFR) AF: 0.000626 AC: 26 AN: 41546

American (AMR) AF: 0.00379 AC: 58 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4826

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00275 AC: 187 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00427 Hom.: 0

Bravo AF: 0.00259

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00391

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (1)
-	-	1	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.63
DANN	Benign	0.49
PhyloP100		-0.71
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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: rs41270237;

hg19: chr2-191851646;