9-35819899-T-A

Variant names:

• chr9-35819899-T-A
• rs766891221
• NM_001012446.4:c.844A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001012446.4(FAM221B):​c.844A>T​(p.Ile282Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 146,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I282V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
• Consequence: FAM221B NM_001012446.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• Publications: 0 publications found

Genes affected

FAM221B (HGNC:30762): (family with sequence similarity 221 member B)

ENSG00000285645 (HGNC:):

TMEM8B (HGNC:21427): (transmembrane protein 8B) Involved in cell-matrix adhesion. Located in cell surface and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21907052).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012446.4. 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
	FAM221B	NM_001012446.4	MANE Select	c.844A>T	p.Ile282Phe	missense	Exon 4 of 7	NP_001012448.2	A6H8Z2-1
	FAM221B	NR_052026.2		n.1305A>T		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM221B	ENST00000423537.7	TSL:1 MANE Select	c.844A>T	p.Ile282Phe	missense	Exon 4 of 7	ENSP00000415299.2	A6H8Z2-1
	FAM221B	ENST00000377984.2	TSL:1	c.844A>T	p.Ile282Phe	missense	Exon 5 of 6	ENSP00000367222.2	F8W8N9
	FAM221B	ENST00000388950.8	TSL:1	n.*12A>T		non_coding_transcript_exon	Exon 5 of 8	ENSP00000373602.4	A6H8Z2-3

Frequencies

GnomAD3 genomes AF: 0.00000681 AC: 1 AN: 146834 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: 0.0000154

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000681 AC: 1 AN: 146834 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71714

African (AFR) AF: 0.00 AC: 0 AN: 41020

American (AMR) AF: 0.00 AC: 0 AN: 14448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3360

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000154 AC: 1 AN: 64932

Other (OTH) AF: 0.00 AC: 0 AN: 2016

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.00095	T
Eigen	Benign	0.015
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.064
Sift	Benign	0.15	T
Sift4G	Benign	0.38	T
Polyphen		0.89	P
Vest4		0.48
MutPred		0.36		Gain of helix (P = 0.0425)
MVP		0.16
MPC		0.44
ClinPred		0.69	D
GERP RS		4.2
Varity_R		0.087
gMVP		0.26
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs766891221; hg19: chr9-35819896;