9-35819283-T-G

Position:

• chr9-35819283-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000423537.7(FAM221B):​c.965A>C​(p.Asp322Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM221B ENST00000423537.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

Genes affected

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

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37674245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM221B	NM_001012446.4	c.965A>C	p.Asp322Ala	missense_variant	5/7	ENST00000423537.7	NP_001012448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM221B	ENST00000423537.7	c.965A>C	p.Asp322Ala	missense_variant	5/7	1	NM_001012446.4	ENSP00000415299	P1
FAM221B	ENST00000388950.8	c.*133A>C		3_prime_UTR_variant, NMD_transcript_variant	6/8	1		ENSP00000373602
TMEM8B	ENST00000377996.5	c.-451+3049T>G		intron_variant		2		ENSP00000367235

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.965A>C (p.D322A) alteration is located in exon 5 (coding exon 4) of the FAM221B gene. This alteration results from a A to C substitution at nucleotide position 965, causing the aspartic acid (D) at amino acid position 322 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.98	N;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.29		Gain of MoRF binding (P = 0.0489);
MVP		0.37
MPC		0.30
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.32
gMVP		0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-35819280;