NM_001077498.3:c.1414G>A

Variant names:

• chr17-28758545-C-T
• rs749227698
• NM_001077498.3:c.1414G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001077498.3(FAM222B):​c.1414G>A​(p.Ala472Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAM222B NM_001077498.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0240
• Publications: 0 publications found

Genes affected

FAM222B (HGNC:25563): (family with sequence similarity 222 member B) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03417495).
• BP6: Variant 17-28758545-C-T is Benign according to our data. Variant chr17-28758545-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3512178.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077498.3. 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
	FAM222B	NM_001077498.3	MANE Select	c.1414G>A	p.Ala472Thr	missense	Exon 3 of 3	NP_001070966.1	Q8WU58
	FAM222B	NM_001288631.2		c.1420G>A	p.Ala474Thr	missense	Exon 4 of 4	NP_001275560.1
	FAM222B	NM_001288632.2		c.1414G>A	p.Ala472Thr	missense	Exon 5 of 5	NP_001275561.1	Q8WU58

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM222B	ENST00000581407.6	TSL:1 MANE Select	c.1414G>A	p.Ala472Thr	missense	Exon 3 of 3	ENSP00000462419.1	Q8WU58
	FAM222B	ENST00000582266.6	TSL:1	c.*1215G>A		3_prime_UTR	Exon 3 of 3	ENSP00000462534.1	J3KSK8
	FAM222B	ENST00000452648.8	TSL:2	c.1414G>A	p.Ala472Thr	missense	Exon 3 of 3	ENSP00000413645.3	Q8WU58

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244674 AF XY: 0.00000751

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: 0.00000754 AC: 11 AN: 1458122 Hom.: 0 Cov.: 30 AF XY: 0.00000965 AC XY: 7 AN XY: 725530

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111808

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.8
DANN	Benign	0.85
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N
PhyloP100		-0.024
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.073
Sift	Benign	0.16	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.075
MutPred		0.13		Gain of glycosylation at A472 (P = 0.0201)
MVP		0.043
MPC		0.11
ClinPred		0.034	T
GERP RS		-6.1
Varity_R		0.055
gMVP		0.31
Mutation Taster		=92/8	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: rs749227698; hg19: chr17-27085563;