NM_001320047.2:c.2342A>C

Variant names:

• chr1-169851914-A-C
• rs149928320
• NM_001320047.2:c.2342A>C

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.2342A>C​(p.Glu781Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,086 control chromosomes in the GnomAD database, including 19 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (13 hom.)
• Consequence: FIRRM NM_001320047.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.14
• Publications: 2 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=0.0033718944).
• BP6: Variant 1-169851914-A-C is Benign according to our data. Variant chr1-169851914-A-C is described in ClinVar as Benign. ClinVar VariationId is 711777.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 6 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.2342A>C	p.Glu781Ala	missense	Exon 24 of 25	NP_001306976.1	Q9NSG2-1
	SCYL3	NM_020423.7	MANE Select	c.*1799T>G		3_prime_UTR	Exon 13 of 13	NP_065156.5
	FIRRM	NM_001366769.1		c.2516A>C	p.Glu839Ala	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.2342A>C	p.Glu781Ala	missense	Exon 24 of 25	ENSP00000352276.4	Q9NSG2-1
	FIRRM	ENST00000286031.10	TSL:1	c.2342A>C	p.Glu781Ala	missense	Exon 23 of 24	ENSP00000286031.6	Q9NSG2-1
	FIRRM	ENST00000413811.3	TSL:1	c.1373A>C	p.Glu458Ala	missense	Exon 22 of 23	ENSP00000389257.3	Q9NSG2-3

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152226 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00185 AC: 465 AN: 251180 AF XY: 0.00179

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00109 AC: 1589 AN: 1461742 Hom.: 13 Cov.: 30 AF XY: 0.00108 AC XY: 786 AN XY: 727174

African (AFR) AF: 0.00251 AC: 84 AN: 33468

American (AMR) AF: 0.000894 AC: 40 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 731 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000487 AC: 542 AN: 1111926

Other (OTH) AF: 0.00305 AC: 184 AN: 60390

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152344 Hom.: 6 Cov.: 31 AF XY: 0.00166 AC XY: 124 AN XY: 74498

African (AFR) AF: 0.00212 AC: 88 AN: 41582

American (AMR) AF: 0.000849 AC: 13 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00209 Hom.: 3

Bravo AF: 0.00193

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00143 AC: 174

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: 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	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0090
DANN	Benign	0.71
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.75	N
PhyloP100		-1.1
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.0040
Sift	Benign	0.46	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.16
MVP		0.12
MPC		0.065
ClinPred		0.00095	T
GERP RS		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.21
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs149928320; hg19: chr1-169821055; COSMIC: COSV107258936;