1-169851821-G-A

Variant names:

• chr1-169851821-G-A
• rs74523449
• NM_001320047.2:c.2249G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001320047.2(FIRRM):​c.2249G>A​(p.Gly750Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,613,748 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (23 hom.)
• Consequence: FIRRM NM_001320047.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.02
• Publications: 7 publications found

Genes affected

FIRRM (HGNC:25565): (FIGNL1 interacting regulator of recombination and mitosis)

SCYL3 (HGNC:19285): (SCY1 like pseudokinase 3) This gene encodes a protein with a kinase domain and four HEAT repeats. The encoded protein interacts with the C-terminal domain of ezrin, an ERM protein, and may play a role in cell adhesion and migration. Alternative splicing results in multiple transcript variants encoding multiple isoforms. [provided by RefSeq, Jun 2012]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004492849).
• BP6: Variant 1-169851821-G-A is Benign according to our data. Variant chr1-169851821-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2639542.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320047.2. 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
	FIRRM	NM_001320047.2	MANE Select	c.2249G>A	p.Gly750Glu	missense	Exon 24 of 25	NP_001306976.1	Q9NSG2-1
	SCYL3	NM_020423.7	MANE Select	c.*1892C>T		3_prime_UTR	Exon 13 of 13	NP_065156.5
	FIRRM	NM_001366769.1		c.2423G>A	p.Gly808Glu	missense	Exon 23 of 24	NP_001353698.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIRRM	ENST00000359326.9	TSL:1 MANE Select	c.2249G>A	p.Gly750Glu	missense	Exon 24 of 25	ENSP00000352276.4	Q9NSG2-1
	FIRRM	ENST00000286031.10	TSL:1	c.2249G>A	p.Gly750Glu	missense	Exon 23 of 24	ENSP00000286031.6	Q9NSG2-1
	FIRRM	ENST00000413811.3	TSL:1	c.1280G>A	p.Gly427Glu	missense	Exon 22 of 23	ENSP00000389257.3	Q9NSG2-3

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 416 AN: 152046 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00297 AC: 746 AN: 251100 AF XY: 0.00315

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00436

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00384 AC: 5611 AN: 1461584 Hom.: 23 Cov.: 30 AF XY: 0.00391 AC XY: 2843 AN XY: 727092

African (AFR) AF: 0.000448 AC: 15 AN: 33446

American (AMR) AF: 0.000738 AC: 33 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00383 AC: 330 AN: 86238

European-Finnish (FIN) AF: 0.00489 AC: 261 AN: 53398

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5760

European-Non Finnish (NFE) AF: 0.00428 AC: 4763 AN: 1111846

Other (OTH) AF: 0.00267 AC: 161 AN: 60380

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152164 Hom.: 4 Cov.: 31 AF XY: 0.00254 AC XY: 189 AN XY: 74392

African (AFR) AF: 0.000650 AC: 27 AN: 41518

American (AMR) AF: 0.000720 AC: 11 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4822

European-Finnish (FIN) AF: 0.00340 AC: 36 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00466 AC: 317 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00356 Hom.: 2

Bravo AF: 0.00237

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00316 AC: 384

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00397

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.0
PROVEAN	Benign	0.040	N
REVEL	Benign	0.020
Sift	Benign	0.43	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.23
MVP		0.40
MPC		0.081
ClinPred		0.0048	T
GERP RS		3.7
Varity_R		0.026
gMVP		0.27
Mutation Taster		=100/0	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: rs74523449; hg19: chr1-169820962; COSMIC: COSV99610357; COSMIC: COSV99610357;