16-67239406-T-A

Variant names:

• chr16-67239406-T-A
• rs751768375
• NM_013241.3:c.250A>T

Variant summary

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

The NM_013241.3(FHOD1):​c.250A>T​(p.Thr84Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. T84A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FHOD1 NM_013241.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.57
• Publications: 0 publications found

Genes affected

FHOD1 (HGNC:17905): (formin homology 2 domain containing 1) This gene encodes a protein which is a member of the formin/diaphanous family of proteins. The gene is ubiquitously expressed but is found in abundance in the spleen. The encoded protein has sequence homology to diaphanous and formin proteins within the Formin Homology (FH)1 and FH2 domains. It also contains a coiled-coil domain, a collagen-like domain, two nuclear localization signals, and several potential PKC and PKA phosphorylation sites. It is a predominantly cytoplasmic protein and is expressed in a variety of human cell lines. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

SLC9A5 (HGNC:11078): (solute carrier family 9 member A5) Predicted to enable potassium:proton antiporter activity and sodium:proton antiporter activity. Predicted to be involved in potassium ion transmembrane transport; regulation of intracellular pH; and sodium ion import across plasma membrane. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. Implicated in end stage renal disease. [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=0.09431422).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013241.3. 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
	FHOD1	NM_013241.3	MANE Select	c.250A>T	p.Thr84Ser	missense	Exon 2 of 22	NP_037373.2	Q9Y613
	FHOD1	NM_001318202.2		c.250A>T	p.Thr84Ser	missense	Exon 2 of 24	NP_001305131.1	A0A068F7M9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHOD1	ENST00000258201.9	TSL:1 MANE Select	c.250A>T	p.Thr84Ser	missense	Exon 2 of 22	ENSP00000258201.4	Q9Y613
	SLC9A5	ENST00000564704.5	TSL:1	n.774+950T>A		intron	N/A
	FHOD1	ENST00000932114.1		c.532A>T	p.Thr178Ser	missense	Exon 4 of 24	ENSP00000602173.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		3.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.043
Sift	Benign	0.073	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.21		Gain of disorder (P = 0.0235)
MVP		0.26
MPC		0.60
ClinPred		0.28	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.28

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: rs751768375; hg19: chr16-67273309;