9-35818913-C-A

Variant names:

• chr9-35818913-C-A
• rs544498652
• NM_001012446.4:c.1148G>T

Variant summary

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

The NM_001012446.4(FAM221B):​c.1148G>T​(p.Arg383Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R383Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FAM221B NM_001012446.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1148G>T	p.Arg383Leu	missense	Exon 6 of 7	NP_001012448.2	A6H8Z2-1
	FAM221B	NR_052026.2		n.1609G>T		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM221B	ENST00000423537.7	TSL:1 MANE Select	c.1148G>T	p.Arg383Leu	missense	Exon 6 of 7	ENSP00000415299.2	A6H8Z2-1
	FAM221B	ENST00000388950.8	TSL:1	n.*316G>T		non_coding_transcript_exon	Exon 7 of 8	ENSP00000373602.4	A6H8Z2-3
	ENSG00000285645	ENST00000650284.1		n.161G>T		non_coding_transcript_exon	Exon 5 of 10	ENSP00000498023.1	A0A3B3IU11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399648 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 690330

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079044

Other (OTH) AF: 0.00 AC: 0 AN: 58074

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.1
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.065
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.46		Loss of MoRF binding (P = 0.0394)
MVP		0.18
MPC		0.36
ClinPred		0.98	D
GERP RS		2.6
Varity_R		0.35
gMVP		0.70
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs544498652; hg19: chr9-35818910;