rs35500644

Variant names:

• chr1-159714095-A-C
• rs35500644
• NM_000567.3:c.105T>G

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_000567.3(CRP):​c.105T>G​(p.Thr35Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,238 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00057 (8 hom.)
• Consequence: CRP NM_000567.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00300
• Publications: 1 publications found

Genes affected

CRP (HGNC:2367): (C-reactive protein) The protein encoded by this gene belongs to the pentraxin family which also includes serum amyloid P component protein and pentraxin 3. Pentraxins are involved in complement activation and amplification via communication with complement initiation pattern recognition molecules, but also complement regulation via recruitment of complement regulators. The encoded protein has a calcium dependent ligand binding domain with a distinctive flattened beta-jellyroll structure. It exists in two forms as either a pentamer in circulation or as a nonsoluble monomer in tissues. It is involved in several host defense related functions based on its ability to recognize foreign pathogens and damaged cells of the host and to initiate their elimination by interacting with humoral and cellular effector systems in the blood. Consequently, the level of this protein in plasma increases greatly during acute phase response to tissue injury, infection, or other inflammatory stimuli. Elevated expression of the encoded protein is associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. [provided by RefSeq, Aug 2020]

ENSG00000297913 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-159714095-A-C is Benign according to our data. Variant chr1-159714095-A-C is described in ClinVar as Benign. ClinVar VariationId is 709552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.003 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00564 (858/152262) while in subpopulation AFR AF = 0.0197 (820/41536). AF 95% confidence interval is 0.0186. There are 11 homozygotes in GnomAd4. There are 418 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000567.3. 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
	CRP	NM_000567.3	MANE Select	c.105T>G	p.Thr35Thr	synonymous	Exon 2 of 2	NP_000558.2	P02741-1
	CRP	NM_001329057.2		c.105T>G	p.Thr35Thr	synonymous	Exon 2 of 3	NP_001315986.1	P02741-1
	CRP	NM_001382703.1		c.105T>G	p.Thr35Thr	synonymous	Exon 2 of 3	NP_001369632.1	Q5VVP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRP	ENST00000255030.9	TSL:1 MANE Select	c.105T>G	p.Thr35Thr	synonymous	Exon 2 of 2	ENSP00000255030.5	P02741-1
	CRP	ENST00000437342.1	TSL:1	c.-307-123T>G		intron	N/A	ENSP00000402788.1	C9JRE9
	CRP	ENST00000368110.1	TSL:3	c.105T>G	p.Thr35Thr	synonymous	Exon 2 of 4	ENSP00000357091.1	Q5VVP7

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 856 AN: 152144 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00137 AC: 339 AN: 248090 AF XY: 0.00111

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000716

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.000567 AC: 828 AN: 1460976 Hom.: 8 Cov.: 31 AF XY: 0.000517 AC XY: 376 AN XY: 726880

African (AFR) AF: 0.0198 AC: 664 AN: 33468

American (AMR) AF: 0.000716 AC: 32 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52650

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111964

Other (OTH) AF: 0.00129 AC: 78 AN: 60370

GnomAD4 genome AF: 0.00564 AC: 858 AN: 152262 Hom.: 11 Cov.: 31 AF XY: 0.00561 AC XY: 418 AN XY: 74474

African (AFR) AF: 0.0197 AC: 820 AN: 41536

American (AMR) AF: 0.00183 AC: 28 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00539 Hom.: 4

Bravo AF: 0.00605

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.7
DANN	Benign	0.47
PhyloP100		0.0030
PromoterAI		0.018	Neutral
Mutation Taster		=96/4	polymorphism

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: rs35500644; hg19: chr1-159683885;